Medical material and hollow fiber membrane module

ABSTRACT

The present invention provides a medical material and a blood purification apparatus each having high anti-thrombotic properties and high safety. The apparatus is produced by incorporating therein a medical material which has a hydrophilic copolymerization polymer present on a surface thereof which is to be in contact with blood, wherein particulate protuberances each having a particle diameter of 50 nm or more are present on the surface which is to be in contact with blood at a density of 3 particles/μm 2  or less and the relaxation time of adsorbed water in the hydrophilic copolymerization polymer is 2.5×10 −8  seconds or shorter and 5.0×10 −10  seconds or longer at −40° C.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Phase application ofPCT/JP2011/080246, filed Dec. 27, 2011, and claims priority to JapanesePatent Application No. 2010-292170, filed Dec. 28, 2010, and JapanesePatent Application No. 2011-087126, filed Apr. 11, 2011, the disclosuresof each being incorporated herein by reference in their entireties forall purposes.

FIELD OF THE INVENTION

The present invention relates to a medical material havinganti-thrombotic properties which can be used suitable in useapplications for which it is required to treat blood or a bloodcomponent, particularly in blood purification apparatus such as anartificial kidney and other use applications for which high levels ofmembrane performance, blood compatibility and safety are required.

BACKGROUND OF THE INVENTION

A medical material to be contacted with a body fluid, such as anartificial blood vessel, a catheter, a blood bag and a blood treatmentapparatus, has been required to have high anti-thrombotic properties.Examples of the blood treatment apparatus include an artificial kidney,an artificial liver, an artificial lung, a blood component adsorbentdevice and a plasma separator. In the present invention, a bloodtreatment apparatus is synonymous with a blood purification apparatus,and a hollow fiber membrane module refers to a hollow fibermembrane-type blood treatment apparatus.

For example, in a hollow fiber membrane for use in an artificial kidney(of which the schematic cross sectional views are shown in FIGS. 1 and2), the deposition of a protein or the deposition/activation ofplatelets can cause the coagulation of blood. When a protein or the likeis deposited onto a membrane, even if led to the coagulation of blood,pores in the membrane are blocked out and become small, resulted in thedeterioration in the performance. When the performance of the membraneis altered rapidly within a short time, there is a concern about theincrease in burden on a living body.

For the purpose of solving these problems, it has been attempted tohydrophylize a hollow fiber membrane and various studies have been madefor this purpose. For example, a method is disclosed, in whichpolyvinylpyrrolidone, which is a hydrophilic polymer, is mixed withpolysulfone in the stage of a membrane forming stock solution and theresulting mixture is molded to thereby impart hydrophilicity to amembrane and protect the membrane from stains (Patent Document 1).However, merely the addition of a hydrophilic component to a membraneforming stock solution cannot achieve a satisfactorydeposition-preventing effect. Then, various improvements have beenattempted. For example, a method in which a vinylpyrrolidone-typepolymer as well as a polyglycol are added to a membrane forming stocksolution to thereby increase the amount of the vinylpyrrolidone-typepolymer present on the inner surface of a membrane (Patent Document 2)and a method in which a vinyl acetate group is provided on the surfaceof a membrane (Patent Document 3) are disclosed. In addition, a methodin which a hydrophilic monomer is graft-polymerized onto the surface ofa material (Non-Patent Document 1) is also disclosed. However, as aresult of the extensive studies made by the present inventors, it isfound that these methods are insufficient for developing anti-thromboticproperties. This is probably because attention is focused only on ahydrophilic polymer on the surface, adsorbed water in the polymer is nottaken into consideration, and the physical configuration of the surfaceof a membrane is insufficient.

Further, in the case of an artificial kidney, after the completion of ablood dialytic therapy, a blood returning procedure in which a salinesolution is allowed to pass through the artificial kidney and bloodremaining in the artificial kidney and the blood circuit is returnedinto the body of a dialysis patient is carried out. However, blood thatcannot be returned into the body is sometimes still remained in theartificial kidney, which is a phenomenon called “residual blood”. Theresidual blood often occurs in an artificial kidney having pooranti-thrombotic properties, can cause anemia in a dialysis patient, andtherefore should be avoided. Heretofore, various improvement methodshave been proposed. As an invention for solving the problem of residualblood induced by the accumulation of blood in a zone that is thefarthest from the center of axis of a main body case 10 (also referredto as “an outer peripheral part”, hereinbelow) in header inner spaces 27and 28 in a blood treatment apparatus 1 as shown in FIG. 2, for example,a method is proposed in which the clearance C between the outerperipheral surface of a hollow fiber membrane bundle 40 and the innerperipheral surface of each of headers 21 and 23 in each of partitioningwall edge faces 31 and 33 is reduced to thereby reduce the accumulationof blood (Patent Documents 4 and 5).

However, as a result of the repeated experiments made by the presentinventors, it is found that the occurrence of residual blood is oftenobserved even in an artificial kidney having a sufficiently smallclearance C and therefore the above-mentioned inventions areinsufficient for solving the problem of residual blood.

Patent Documents

-   Patent Document 1: Japanese Patent Publication No. 2-18695-   Patent Document 2: Japanese Patent Laid-open Publication No.    6-165926-   Patent Document 3: Japanese Patent Laid-open Publication No.    4-300636-   Patent Document 4: Japanese Patent Laid-open Publication No. 63-9448-   Patent Document 5: Japanese Patent Laid-open Publication No.    10-165777

Non-Patent Document

Non-Patent Document 1: Chiaki Yoshikawa et al. Macromolecules 2006, 39,2284-2290

SUMMARY OF THE INVENTION

The present invention provides a medical material and a bloodpurification apparatus both having high anti-thrombotic properties andhigh safety.

The present inventors have made extensive studies for the purpose ofsolving the above-mentioned problems. As a result, it is found that amedical material and a hollow fiber membrane module both having highanti-thrombotic properties and high safety can be achieved by thefollowing constitutions.

[1] A medical material having a hydrophilic copolymerization polymerpresent on a surface thereof which is to be in contact with blood(hereinbelow, also referred to as “a blood-contacting surface” forconvenience), wherein particulate protuberances each having a particlediameter of 50 nm or more are present on the blood-contacting surface ata density of 3 particles/μm² or less and the relaxation time of adsorbedwater in the hydrophilic copolymerization polymer is 2.5×10⁻⁸ seconds orshorter and 5.0×10⁻¹⁰ seconds or longer at −40° C.

It is preferred that a flexible layer is present on the blood-contactingsurface when the material is in a moistened state and the flexible layerhas a thickness of 7 nm or more.

It is preferred that the amount of the hydrophilic copolymerizationpolymer on the blood-contacting surface is 5 to 30% by weight inclusive.

As an embodiment of the medical material, a hollow fiber membrane can bementioned, and a hollow fiber membrane module having a medical materialincorporated therein can be used as an artificial kidney or the like.

As the polymer that constitutes the material, a polysulfone-type polymercan be used preferably.

[2] In the present invention, attention is focused on the overallimprovement of anti-thrombotic properties of the hollow fiber membranemodule, and it is found that a hollow fiber membrane module in which thehollow fiber membrane filling rate in a zone lying between an outermostperiphery and a position located 1 mm apart from the outermost peripherytoward an inner periphery in a module edge face part is 15% or more andthe difference between the hollow fiber membrane filling rate in thezone and that in a center part is 40% or less enables the drasticimprovement of the accumulation of blood in an outer peripheral part ofthe module.

[3] Another embodiment according to the present invention is examinedmore in detail with attention focused on the distribution andarrangement of hollow fiber membranes in the hollow fiber membranemodule [2]. As a result, it is found that the improvement ofaccumulation of blood can be achieved more reliably by optimizing theconstitution of the hollow fiber membrane module [2] as follows.

“A hollow fiber membrane module comprising: a hollow fiber membranebundle; a main body case in which the hollow fiber membrane bundle isstored; partitioning walls which enable the hollow fiber membrane bundleto be held in a liquid-tight state at both ends of the main body casewhile keeping the hollow part edge faces in an opened state; and headerswhich are respectively attached both ends of the main body case andthrough which blood can be introduced and led out;

wherein the hollow fiber membrane filling rate in each of zones A to H,which are zones produced by dividing a zone lying between a positioncorresponding to the inner diameter of each of the headers and aposition 1 mm apart from the aforementioned position toward the innerperiphery into equal 8 parts equiangular with the center of axis of themain body case as its center in an edge face of each of the partitioningwalls on a side facing each of the headers, falls within the range from13 to 40%.

In the above-mentioned embodiment, the effect can become maximum bycombining with a technique of arranging a hydrophilic copolymerizationpolymer having a relaxation time of adsorbed water of 2.5×10⁻⁸ secondsor shorter and 5.0×10⁻¹⁰ or longer at −40° C. on a blood-contactingsurface of each of the hollow fiber membranes.

If particulate protuberances each having a particle diameter of 50 nm ormore are present on the blood-contacting surface of each of the hollowfiber membranes at a density of more than 3 particles/μm², the bloodaccumulation effect cannot be developed greatly. Further, it ispreferred that a flexible layer is present when the material is in amoistened state and the flexible layer has a thickness of 7 nm or more.It is also preferred that the amount of the hydrophilic copolymerizationpolymer on the blood-contacting surface of each of the hollow fibermembranes is 5 to 30% by weight inclusive.

The term “inner diameter of a header” as used herein refers to a valuethat is determined on a cross section taken at a position that overlapsan edge surface on a side facing a header of a partitioning wall. Whenthe header diameter is altered on the cross section, the minimum valueof the varied header diameters is defined as the “header innerdiameter”. When the header is provided with a ring-shaped elastic bodysuch as an O-ring and the ring-shaped elastic body is in contact withthe partitioning wall in the innermost periphery side thereof, thediameter at the position of the ring-shaped elastic body is defined asthe “header inner diameter”. The term “inner diameter of body part of amain body case” as used herein refers to a value that is determined on across section on which the inner diameter becomes minimum in the bodypart of the main body case.

The medical material according to the present invention has highanti-thrombotic properties and high safety. Particularly in anartificial kidney, when a hollow fiber membrane having highanti-thrombotic properties is used, the accumulation of blood in a zonethat is the farthest from the center of the axis of a main body case ina header internal space is reduced and therefore it becomes possible toprovide an artificial kidney having improved membrane performance andexcellent residual blood performance.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic cross sectional view of an embodiment of ablood treatment apparatus.

FIG. 2 shows a schematic cross sectional view illustrating an embodimentof a blood treatment apparatus more in detail.

FIG. 3 shows a curve illustrating the relationship between the forceacting on a cantilever and the displacement amount of the cantilever ina force curve measurement using an atomic force microscope.

FIG. 4 shows a schematic view of a zone of which the filling rate is tobe measured at an partitioning wall edge face.

FIG. 5 shows a schematic view of an embodiment of a crimp structure of ahollow fiber membrane.

FIG. 6 shows a circuit to be used in a clearance measurement.

FIG. 7 shows an example of a scanning electron micrograph of a surfacein a hollow fiber membrane.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The invention of the present application has been accomplished on thebasis of a finding that not only the physical structure but also thecomposition of the surface of a medical material are important forimproving the anti-thrombotic properties of the medical material.

The medical material according to the invention of the presentapplication contains a hydrophilic copolymerization polymer. The“hydrophilic” polymer in the hydrophilic copolymerization polymer refersto a polymer that contains at least one hydrophilic unit and can bedissolved in an amount of 0.1 g or more in 100 g of water at 20° C. Thatis, the hydrophilic copolymerization polymer is a polymer in whichmultiple monomer units are bound together by copolymerization, whereinat least one of the monomer units is a hydrophilic unit.

The medical material refers to a material to be used in a medical devicethat contacts with a body fluid, such as an artificial blood vessel, acatheter, a blood bag and a blood treatment apparatus. Examples of theblood treatment apparatus include an artificial kidney, an artificialliver, an artificial lung, a blood component adsorbent device and aplasma separator. As for the material, a polysulfone-type polymer suchas polysulfone, polyethersulfone and polyarylate, polystyrene,polyethylene, polypropylene, polycarbonate, polyurethane, polyvinylchloride, an acrylic resin such as polymethyl methacrylate, afluororesin such as polyvinylidene fluoride, polyacrylonitrile, apolyester such as polyethylene terephthalate, and a polyamide can beused suitably. The material may be copolymerized with other monomer ormay be modified, as long as the effect of the invention of the presentapplication is not hindered. The preferred amount of the othercopolymerization monomer is, but not limited to, 10% by weight or less.

When the hydrophilic polymer is present on the surface, a diffuse layeris formed on the surface. It is known that the deposition of a bloodcomponent can be inhibited by the excluded volume effect of the diffuselayer. The inventors of the present application found that the excludedvolume effect of a diffuse layer containing a hydrophilic copolymerizedcopolymer is higher than a diffuse layer containing a hydrophilichomopolymer. This is probably because, for example in a homopolymer suchas polyvinylpyrrolidone (PVP), the interaction between pyrrolidone ringsis too strong, and therefore the intermolecular or intramolecularrestraint becomes large and the turning radius of a molecular chainbecomes small, resulted in insufficient development of the excludedvolume effect of the diffuse layer.

In addition, as the result of the intensive studies made by theinventors of the present application, it is found that the deposition ofa blood component is sometimes inhibited insufficient only by theexcluded volume effect. It is found that adsorbed water of thehydrophilic copolymerization polymer is important for overcoming thisproblem. The term “adsorbed water” refers to water which interacts withthe polymer and of which the mobility is lowered (i.e., has a longerrelaxation time) compared with that of bulk water. In the invention ofthe present application, the relaxation time of the adsorbed water inthe hydrophilic copolymerization polymer is preferably 2.5×10⁻⁸ secondsor shorter, preferably 2.0×10⁻⁸ seconds or shorter, and 5.0×10⁻¹¹seconds or longer, preferably 8.0×10⁻¹¹ seconds or longer at −40° C.Although the reason why the relaxation time of the adsorbed water isconsidered to be important is unclear, since the relaxation time of theadsorbed water is about 10⁻⁹ to 10⁻¹⁰ seconds, it is considered that theinfluence of the surface of the membrane on a protein is small when themobility of the adsorbed water in the protein is close to the mobilityof the adsorbed water in the surface of the membrane.

The relaxation time of adsorbed water is a value obtained by adielectric relaxation measurement, and is measured by cooling an aqueoushydrophilic copolymerization polymer solution having a concentration of20% by weight or more to −40° C. The reason to cool to −40° C. isbecause bulk water is frozen at that temperature and therefore themeasurement of adsorbed water can be performed easily. When ahydrophilic copolymerization polymer which cannot be dissolved at aconcentration of 20% by weight or more is used, the measurement may becarried out using a suspended aqueous solution.

As for the hydrophilic copolymerization polymer having adsorbed water, ahydrophilic copolymerization polymer comprising a water-soluble unit anda hydrophobic unit is preferably used. The term “water-soluble unit” asused herein refers to a unit that is included within the range of theabove-mentioned hydrophilic unit and has a high water solubility, and isa homopolymer of the above-mentioned unit which can be dissolved in anamount of 10 g or more in 100 g of water at 20° C. The “hydrophobicunit” as used herein refers to a unit that is a homopolymer of theabove-mentioned unit and can be dissolved in an amount of less than 0.1g in 100 g of water at 20° C. Examples of the water-soluble unit includevinylpyrrolidone, vinyl alcohol and ethylene glycol. Examples of thehydrophobic unit include vinylcaprolactam, propylene glycol, vinylacetate, styrene, hydroxyethyl methacrylate and methyl methacrylate.

Although the reason why a hydrophilic copolymerization polymercomprising a water-soluble unit and a hydrophobic unit is proffered isunclear, it is assumed as follows: the interaction of a hydrophiliccopolymerization polymer comprising only a water-soluble unit with awater molecule is too strong and therefore the mobility of adsorbedwater is deteriorated, but a water molecule can be unstabilized when ahydrophobic unit is present and therefore the mobility of a watermolecule present around a hydrophilic unit can be improved. If only ahydrophobic unit is contained, it is considered that the hydrophobicinteraction becomes too strong and therefore the denaturation of aprotein may be induced. For these reasons, with respect to the type ofthe copolymerization polymer, an alternating copolymerization polymer ora random copolymerization polymer can be used more suitably than a graftcopolymerization polymer or a block copolymerization polymer. In thisregard, a copolymerization polymer cannot be regarded as a blockpolymer, unless an average of 10 units each of which is one of theconstituent units of the copolymerization polymer and is contained at asmaller component ratio exists contiguously.

The (molar) ratio of the hydrophobic unit to all of units is preferably0.3 to 0.7 inclusive. Particularly preferably used are avinylpyrrolidone-vinylcaprolactam copolymerization polymer, avinylpyrrolidone-vinyl acetate copolymerization polymer, avinylpyrrolidone-hydroxyethyl methacrylate copolymerization polymer,vinylpyrrolidone-methyl methacrylate and ethylene glycol-polypropyleneglycol. The copolymer may be of a two-component type or amulti-component type.

If the amount of the hydrophilic copolymerization polymer on the surfaceof the material is too small, the deposition of a blood component cannotbe prevented. If the amount is too large, on the contrary, there is aconcern about the elution of the hydrophilic copolymerization polymer.Further, in this case, the smoothness of the surface is lost and thesurface becomes largely uneven. As a result, the number of particulateprotuberances each having a particle diameter 50 nm or more isincreased. Therefore, the amount of the hydrophilic copolymerizationpolymer present on the surface is preferably 5% by weight or more, morepreferably 8% by weight or more, still more preferably 10% by weight ormore, and is preferably 30% by weight or less, more preferably 20% byweight or less, still more preferably 15% by weight or less. When thematerial is used for an artificial kidney, when the hydrophobicity ofthe hollow fiber membrane is increased, water permeation performance isdeteriorated and therefore the performance of the membrane isdeteriorated. From this viewpoint, a too large amount of the hydrophiliccopolymerization polymer is not preferred. It is also preferred that thehydrophilic copolymerization polymer exists only on the blood-contactingsurface. Therefore, for the purpose of keeping high membraneperformance, it is important that the ratio of the amount of thehydrophilic copolymerization polymer (also referred to as a “polymeramount”, hereinbelow) present in an inner surface, which is ablood-contacting surface, of the hollow fiber membrane is larger thanthat on an outer surface of the hollow fiber membrane. The amount ratioof the hydrophilic copolymerization polymer in the inner surface ispreferably larger by 1.1 times, preferably 2 times, more preferably 5times or more, than that in the outer surface. The ratio of the amountof the hydrophilic copolymerization polymer in the outer surface is lessthan 10% by weight, preferably less than 5% by weight.

The reason why it is necessary to provide the flexible layer on theblood-contacting surface when the material is in a moistened state isassumed as follows: platelets and blood cells are less likely to getcloser to the material and are less likely to be deposited or activatedwhen the flexible layer that constitutes the material becomes thicker.If the flexible layer is too thick, on the contrary, a protein might betrapped by the flexible layer. For these reasons, the thickness of theflexible layer is preferably 5 nm or more, more preferably 7 nm or more,and is preferably 30 nm or less, more preferably 20 nm or less, stillmore preferably 15 nm or less. The moistened state refers to a state inwhich the water content is 65% by weight or more.

The thickness of the flexible layer on the surface of a separationmembrane functional layer in a moistened state can be calculated by aforce curve measurement using an atomic force microscope. A force curveis expressed by a displacement amount of a cantilever on a horizontalaxis wherein the force acting on the cantilever is plotted on thevertical axis. Until a shorter hand of the cantilever is in contact withthe surface of the functional layer, the force curve is shifted inparallel with the x-axis. After the cantilever contacts with the surfaceof the functional layer, when there exists the flexible layer, a curvednon-linear part appears. Thereafter, a linear relationship is obtainedbetween the displacement force of the cantilever and the force of thecantilever. The thickness of the flexible layer is defined as a distancefrom an intersection point between an extended line of a part thatbecomes linear after the contact of the shorter hand of the cantileverwith the surface and an extension of a line that is shifted in parallelwith the x-axis before the contact of the shorter hand of the cantileverwith the surface to a point at which the shorter hand of the cantilevercontacts with the surface (FIG. 3).

Examples of the method for producing the material having a surface ofthe flexible layer thickness include: a method of coating thehydrophilic copolymerization polymer onto the surface of the material; amethod of immobilizing the hydrophilic copolymerization polymer onto thesurface of the material by cross-linking; and a method of blending thehydrophilic copolymerization polymer to a polymer stock solution forforming the medical material and molding the resulting blend.

When a post-treatment is carried out using the hydrophiliccopolymerization polymer by coating or the like, the concentration ofthe hydrophilic polymer in the coating solution, the time of contact andthe temperature employed for the coating affect the (surface) amount ofthe polymer coated or the like and so on. For example, the coating iscarried out using a solution of a vinylpyrrolidone-vinylcaprolactamcopolymerization polymer, a vinylpyrrolidone-vinyl acetatecopolymerization polymer or ethylene glycol-polypropylene glycol, theconcentration in the aqueous solution is preferably 1 to 5000 ppm, thecontact time is preferably 10 seconds or longer, and the temperature ispreferably 10 to 80° C. In the case where the coating is carried out ina continuous mode, not in a batch mode, the aqueous coating solution canbe coated more uniformly when the flow rate of the aqueous coatingsolution is higher. However, the flow rate is too rapid, a sufficientamount cannot be coated. Therefore, the flow rate is preferably fallswithin the range from 200 to 1000 mL/min. When the coating is carriedout in this range, a uniform coating can be achieved. A care should betaken not to form an uneven coating, unless protruding objects may beformed.

When the hollow fiber membrane is coated, it is preferred that thehydrophilic copolymerization polymer is applied onto only theblood-contacting surface of the hollow fiber membrane. In the case of anartificial kidney or the like, the inside of the hollow fiber membranecorresponds to the blood-contacting surface. Therefore, a method inwhich a difference in pressure is produced from the inside of the hollowfiber membrane toward the outside of the hollow fiber membrane to coatthe hollow fiber membrane with the hydrophilic copolymerization polymeris preferred, since the hydrophilic copolymerization polymer can beintroduced efficiently onto the inner surface of the hollow fibermembrane. The difference in pressure is preferably 10 mmHg or more, morepreferably 50 mmHg or more, between the coating solution inlet side (theinside of the hollow fiber) and the coating solution outlet side (theoutside of the hollow fiber) in the hollow fiber membrane module.Further, a procedure for allowing a gas (e.g., compressed air), water,an aqueous solution that does not contain the hydrophiliccopolymerization polymer or the like to flow in a direction opposite tothe direction of the coating of the hydrophilic polymer (i.e., in adirection from the outside of the hollow fiber toward the inside of thehollow fiber) is a particularly preferred technique, since the procedureenables the concentration of the polymer that is one-layer-coated onlyon the inner surface. The flow rate of a gas (e.g., compressed air) tobe flow from the outside of the hollow fiber toward the inside of thefollow fiber is preferably 70 NL/min or less, more preferably 50 NL/minor less, and the gas is preferably allowed to flow for 10 minutes orshorter. In the case of water or an aqueous solution, the water or theaqueous solution is preferably allowed to flow at a flow rate of 1 L/minor less, more preferably 0.5 L/min or less, preferably for 1 minute orshorter. An operation of pressurizing the outside of the hollow fibermembrane to blow a gas into the inside of the hollow fiber membraneintermittently is preferred, since an excess portion of the polymer canget brown and can be removed and therefore uniform coating can beachieved. The term “intermittently” as used herein refers to a matterthat the increase and decrease of the flow rate of the gas is alteredrepeatedly while varying a pressure, and it is preferred to repeat theblowing at a highest pressure and the blowing at a lowest pressurewithin a certain fluctuation range. The ratio of the largest flow rateto the smallest flow rate or the ratio of the highest pressure to thelowest pressure is preferably 1.5 times or more, more preferably 2 timesor more. The smallest flow rate of the gas to be flown through theinside of the hollow fiber membrane is preferably 0.1 NL/min or more and10 NL/min or less, and the largest flow rate is preferably 0.15 NL/minor more and 30 NL/min or less.

When only the coating is performed, the hydrophilic copolymerizationpolymer may be eluted from the material as used. Therefore, it ispreferred to perform cross-linking with heat or a radioactive ray afterthe coating. However, if the cross-linking is performed merely by theirradiation with a radioactive ray, the state of water adsorbed onto thehydrophilic copolymerization polymer may be altered. Then, γ-ray orelectron beam is employed as the radioactive ray. When γ-ray isemployed, the preferred dose range is 2500000 to 10000000 Ci or more,preferably 3000000 to 7500000 Ci. When electron beam is employed, theacceleration voltage is 5 MeV or more, preferably 10 MeV or more. Thepreferred dose of irradiation is 5 to 50 kGy, preferably 10 to 35 kGy,and the preferred temperature for irradiation is 10 to 60° C.,preferably 20 to 50° C. It is also preferred to perform the irradiationwith the radioactive ray within two weeks, preferably one week, afterthe coating. After the coating, it is desirable that the coated productis stored at 0° C. to 60° C., preferably 5 to 50° C. or lower and thenis immediately subjected to a cross-linking treatment with theradioactive ray. When heating is required for convenience of theprocess, it is desirable to carry out the heating within a short time.Specifically, when the heating is carried out at 100° C. or higher, thetime for the heating is preferably 10 minutes or shorter. This isbecause the state of the polymer existing on the surface may be alteredafter the coating due to the molecular motion of the polymer or thelike. Further, if an ion is present, the state of adsorbed water is alsoaltered. Therefore, it is preferred that any inorganic ion such as asodium ion and a calcium ion is not present during the irradiation withthe radioactive ray. Specifically, when the material is in a moistenedstate, the concentration of ions in water is preferably 1000 ppm orless, more preferably 100 ppm or less. The amount of water to becontained in the material is 6 times or less, preferably 4 times orless, the dried weight of the material. The material may be irradiatedwith the radioactive ray in a dried state (i.e., a state in which thematerial is not moistened with water), but the amount of water to becontained in the material is preferably 0.05 time or more the driedweight of the material.

For the purpose of controlling the cross-linking, an antioxidant agent,i.e., a radical trap agent as used in the present invention, may beused. The term “radical trap agent” as used herein refers to a moleculethat has a property of being likely to donate an electron to anothermolecule. Examples of the radical trap agent include, but not limitedto: a water-soluble vitamin such as vitamin C; a polyphenol; an alcoholsuch as methanol, ethanol, propanol, ethylene glycol, propylene glycoland glycerin; a saccharide such as glucose, galactose, mannose andtrehalose; an inorganic salt such as sodium hydrosulfite, sodiumpyrosulfite and sodium dithionate; uric acid; cysteine and glutathione.When an inorganic salt is used, a careful attention should be paid tothe upper limit of the concentration to be added, as stated above. Theseradical trap agents may be used singly, or a mixture of two or more ofthe radical trap agents may be used. The radical trap agent ispreferably added in the form of an aqueous solution. In this case, theoxygen concentration in the aqueous solution is preferably 10 mg/L orless, more preferably 5 mg/L or less, since oxygen dissolved in theaqueous solution or oxygen in the atmosphere can accelerate oxidativedecomposition. The oxygen concentration in the gas to be contacted withthe separation membrane upon the irradiation with the radioactive ray ispreferably 5% or less, more preferably 3% or less. Among theabove-mentioned radical trap agents, a monohydric alcohol such asethanol, propanol, butanol, pentanol and hexanol is preferably used.When ethanol, n-propanol or 2-propanol is used, the concentration in theaqueous solution is preferably 0.01% by weight or more and 10% by weightor less, more preferably 0.05% by weight or more and 1% by weight orless. When propylene glycol or glycerin is used, the concentration ispreferably 0.1% by weight or more and 90% by weight or less, morepreferably 0.5% by weight or more and 70% by weight or less.

Next, the method for blending the hydrophilic copolymerization polymerto a polymer stock solution for medical material molding purposes andmolding the resulting blend is described. For example, for a hollowfiber membrane, a method for spinning a membrane forming stock solutioncomprising a polysulfone-type polymer and the hydrophiliccopolymerization polymer is employed. In this case, a third componentsuch as PVP may be added. Further, the hydrophilic copolymerizationpolymer may be added to a core injection solution during the formationof a membrane of the hollow fibers. A method in which a polysulfone-typehollow fiber membrane is molded and then the hydrophiliccopolymerization polymer is introduced into the surface of the hollowfiber membrane by a post-treatment is also one of preferred methods.

When the hydrophilic copolymerization polymer is added to the membraneforming stock solution, the spinning conditions are as follows: the moldtemperature preferably ranges from 30 to 60° C., the temperature of adry unit preferably ranges from 20 to 50° C., and the relative humiditypreferably ranges from 70 to 95% RH. The temperature of the dry unit ispreferably lower than the mold temperature, more preferably lower by 10°C. or more than the mold temperature. The length of the dry unit ispreferably 10 to 100 cm. The mold temperature is preferably the same asthe storage temperature for the membrane forming stock solution orlower. This is because the structure of a polymer is established with athermal history left therein when the temperature at a discharge part isincreased, which is undesirable because distortion may remain inmolecules of the polymer after the molding.

For the purpose of allowing the hydrophilic copolymerization polymer toexist in the inner surface of the hollow fiber membrane in a largeramount than that in the outer surface of the hollow fiber membrane, itis preferred to use a mixed solution of a good solvent and a poorsolvent for the polysulfone-type polymer in a coagulating bath. Examplesof the good solvent include N,N′-dimethylacetamide (DMAc) andN-methylpyrrolidone, and examples of the poor solvent include water andan alcohol. The concentration of the good solvent to be employed ispreferably 10% by weight or more, more preferably 15% by weight or more,and is preferably 30% by weight or less, more preferably 25% by weightor less.

A method in which the outer surface of the hollow fiber membrane iswashed with water, an aqueous DMAc solution or the like in a spinningstep to reduce the amount of the hydrophilic copolymerization polymer inthe outer surface of the hollow fiber membrane is preferred.

When the hydrophilic copolymerization polymer is added to the coreinjection solution, the content ratio of the core injection solution,the temperature of the core injection solution, the composition of themembrane forming stock solution and the like affect the amount of thehydrophilic copolymerization polymer in the surface of the hollow fibermembrane. For example, when a vinylpyrrolidone-vinyl acetatecopolymerization polymer is added to the core injection solution andthen the resulting core injection solution is added to a membraneforming stock solution comprising polysulfone and PVP, the amount to beadded to the core injection solution is preferably 5 to 30% by weight,the temperature of the core injection solution is preferably 10 to 60°C., and the membrane forming stock solution preferably has such acomposition in which the polysulfone concentration is 14 to 25% byweight and the PVP concentration is 2 to 10% by weight. For improvingthe remainability of the vinylpyrrolidone-vinyl acetate copolymerizationpolymer on the surface of the membrane, polysulfone preferably has asmaller weight average molecular weight and polysulfone having a weightaverage molecular weight of 100000 or less, preferably 50000 or less,can be used suitably.

In the present invention, it is found that the deposition of a bloodcomponent cannot be sometimes controlled satisfactorily merely byoptimizing the surface composition of the material. Then, the physicalstructure of the surface of the material is examined and attention isparticularly focused on particulate protuberances on the surface. Theparticulate protuberances are formed from a polymer that mainlyconstitutes the material. In the invention of the present application,it is found that the content ratio of particulate protuberancesparticularly each having a particle size (particle diameter) of 50 nm ormore present on the inner surface of the membrane is 3 particles/μm² orless, preferably 2 particles/μm² or less, more preferably 1 particle/μm²or less. When each of the particulate protuberances is not circular andis oval, the particle diameter is defined as the major axis, i.e., thelongest diameter. When the protuberances have irregular shapes and it isimpossible to determine the major axis, the diameter can be determinedby calculating the area of each of the protuberances and then convertinginto its equivalent in a circular shape (i.e., an equivalent circlediameter). That is, when many particulate protuberances are present, thedeposition of a blood cell component is induced. The reason for this isassumed that platelets can be deposited easily due to the physicalstimuli from the protuberances on the cell membrane or the like. If theamount of the hydrophilic copolymerization polymer on the surface isincreased, protuberances may be formed easily. In addition, if thecoating amount of the hydrophilic copolymerization polymer on thesurface of the material is uneven, areas in which the amount of thehydrophilic copolymerization polymer is large occur on the surface andtherefore protuberances may be formed easily. When the medical materialis a hollow fiber membrane for a blood purification apparatus, if manyprotuberances are present on the surface of the membrane, the flow onthe surface of the membrane is disturbed and therefore the filmresistance of the membrane is decreased. From the viewpoint of themembrane performance, it is preferred that the abundance ratio of theparticulate protuberances is high and is preferably 0.1 particle/μm² ormore, more preferably 0.2 particle/μm² or more. In the case of a bloodpurification apparatus, since the number of contacts of platelets withthe material is restricted due to the flow of blood, it is consideredthat the influence of protuberances is smaller compared with a medicalmaterial that is indwelled in the body.

The confirmation on the existence of the particulate protuberances onthe surface of the material is carried out by the magnifying observationat a magnification of 50000 times on a scanning electron microscope.

The development of the particulate protuberances on the surface isaffected by the state of dispersion of the polymer in the membraneforming stock solution, the state of phase separation during spinningand the like. Therefore, for reducing the particulate protuberances onthe surface of the membrane, it is very preferred that a hydrophilicpolymer having good compatibility with the polysulfone-type polymer isadded to the membrane forming stock solution. Specific examples of thehydrophilic polymer include PVP, polyethylene glycol, polyvinyl alcoholand derivatives thereof.

In the membrane forming stock solution, the concentration of thepolysulfone-type polymer is preferably 14 to 25% by weight, morepreferably 15 to 20% by weight, and the concentration of the hydrophilicpolymer is preferably 2 to 10% by weight, more preferably 3 to 9% byweight. The ratio of the weight of the hydrophilic polymer relative tothe total weight of all of the polymers contained in the membraneforming stock solution is preferably 0.15 to 0.35 time, more preferably0.2 to 0.3 times. The polysulfone-type polymer preferably has a weightaverage molecular weight of 30000 or more, and ratio of the weightaverage molecular weight of the hydrophilic polymer is preferably largerby 15 to 40 times, more preferably 20 to 35 times, than that of thepolysulfone-type polymer.

It is preferred to agitate the membrane forming stock solution at a highagitation speed, since the state of dispersion of the hydrophilicpolymer and the polysulfone-type polymer becomes uniform. The speed ofan impeller is preferably 30 rpm or more, more preferably 50 rpm ormore. If the dissolution temperature is low, uniform microdispersioncannot be achieved. If the dissolution temperature is too high, thedecomposition of the polymer may be caused. Therefore, the dissolutiontemperature is preferably 60° C. or higher, more preferably 80° C. orhigher, and is preferably 120° C. or lower, more preferably 100° C. orlower. Over time, the microphase separation begins to start in themembrane forming stock solution and the hydrophilic polymer cannot bemicrodispersed uniformly. Therefore, it is preferred to spin thesolution within 80 hours after the dissolution. The storage temperatureafter the dissolution is preferably 45° C. or higher, more preferably60° C. or higher, and is preferably 90° C. or lower, more preferably 80°C. or lower.

With respect to the spinning conditions, the mold temperature ispreferably 30 to 60° C., the temperature of the dry unit is preferably20 to 50° C., the relative humidity is preferably 70 to 95% RH. Thetemperature of the dry unit is preferably lower, preferably by 10° C. ormore, than the mold temperature. The length of the dry unit ispreferably 10 to 100 cm. The mold temperature is preferably equal to orlower than the storage temperature for the membrane forming stocksolution. For the coagulating bath, a mixed solution of a good solventand a poor solvent for the polysulfone-type polymer is preferably used.Examples of the good solvent include DMAc and N-methylpyrrolidone.Examples of the poor solvent include water and an alcohol. Theconcentration of the good solvent is 10% by weight or more, preferably15 to 30% by weight inclusive, and preferably 25% by weight or less. Thetemperature of the coagulating bath is preferably 20° C. or higher and60° C. or lower.

If the hollow fiber membrane is dried after the formation thereof,particulate protuberances are likely to be produced and therefore acareful attention should be paid. That is, it is considered thatparticulate protuberances are formed when the membrane is shrunk uponbeing dried. It is preferred to employ a rapid drying rate, since themembrane can be dried before the formation of the protuberances andtherefore the number of the protuberances on the surface of the membranecan be reduced. If a slow drying rate is employed, on the other hand,the protuberances are likely to be formed, since there is a time forcausing the change in configuration of the surface of the membrane.Therefore, the drying temperature is preferably 200° C. or lower, morepreferably 170° C. or lower, still more preferably 150° C. or lower, andis preferably 90° C. or higher, more preferably 100° C. or higher, stillmore preferably 110° C. or higher. It is also preferred to apply acertain degree of tensile force to the hollow fiber membrane duringdrying, from the viewpoint of the reduction in protuberances formed. Thetensile force to be applied immediately before the drying step ispreferably 15 g/mm² or more, more preferably 50 g/mm² or more. If thetensile force is too high, the performance of the membrane may bealtered. Therefore, the tensile force is preferably 500 g/mm² or less,more preferably 250 g/mm² or less.

The hollow fiber membrane module has multiple pieces of the hollow fibermembranes incorporated therein. If such a drift of blood flow that bloodflows in a larger amount in some of the hollow fiber membranes occurs,even if the performance of the individual hollow fiber membranes ishigh, high overall performance of the module cannot be achieved.Further, if such the drift of blood flow occurs, a problem of so-called“occurrence of residual blood” may arise. The term “occurrence ofresidual blood” as used herein refers to such a phenomenon that bloodremains in the module when blood in a circuit or a module is returnedinto a body after a dialytic therapy. The occurrence of residual bloodin clinical practice is induced by a cause other than the drift of bloodflow, e.g., the deposition of platelets or the like onto the membrane,and is considered as a measure for the overall anti-thromboticproperties of the hollow fiber membrane module.

In the present invention, it is found that the distribution of thehollow fiber membranes on the transverse section of the hollow fibermembrane module is also a critical factor for solving theabove-mentioned problem.

That is, the filling rate in a zone lying between the outermostperiphery of the edge face part of the hollow fiber membrane module anda position located 1 mm apart from the outermost periphery toward theinner periphery is preferably 15 or more, more preferably 20% or more.If the filling rate exceeds 40%, the opening of the hollow fibermembrane 41 may be closed with a contact surface 25 that contacts with apartitioning wall of a header. The outermost periphery of the edge facepart corresponds to the inner peripheral surface of a case of the modulein which the hollow fiber membranes are stored. When the diameter of theinner peripheral surface of the header is smaller than that of the case,since a zone lying between the case inner peripheral surface and aposition 1 mm apart from the inner peripheral surface toward the innerperiphery is filled with a ring-shaped elastic body or the like, thehollow fiber membranes are not arranged generally. Therefore, in thiscase, a header inner peripheral surface is deemed as a case innerperipheral surface. An edge face part is a face on which edge parts ofhollow fiber membranes exist, and refers to an outer partitioning walledge face part when the edge parts of the hollow fiber membranes arefixed by means of a partitioning wall at the edge part of the casing. Inthe present invention, it is preferred that the difference between thehollow fiber membrane filling rate in a zone lying between the outermostperiphery and a position 1 mm apart from the outermost periphery (anoutermost periphery zone) and the hollow fiber membrane filling rate inthe center part is within 40%, preferably within 30%. The term “centerpart” as used herein refers to a cylindrical internal zone having aradius that is half of the distance between the center point of the caseand the inner peripheral surface of the case. When the radius of theheader inner peripheral surface is smaller than that of the case innerperipheral surface as mentioned above, the radius of the center part maybe half of the distance between the case center point and the headerinner peripheral surface.

With respect to the overall filling rate (a filling rate in a bodypart), the lower limit is limit is preferably 53% or more, morepreferably 55% or more, still more preferably 57% or more, and the upperlimit is preferably 64% or less, more preferably 62% or less, still morepreferably 60% or less.

The position at which the filling rate is to be measured may be anyposition other than a position in which a potting material is filled(e.g., a module end). Details of the method for measuring the fillingrate are as mentioned in the section “Examples” below.

If the difference between the fiber filling rate in the outermostperipheral zone and the filling rate in the center part is too large,blood is likely to flow in fibers located in the center part andtherefore blood is likely to be accumulated in the outer peripheralpart. As a result, the activation of blood may be induced or the modulemay not exhibit its performance sufficiently.

Further, it is more preferred that the hollow fiber membrane fillingrate in each of zones A to H, which are zones produced by dividing azone lying between a position corresponding to the inner diameter ofeach of the headers and a position 1 mm apart from the aforementionedposition toward the inner periphery into equal 8 parts equiangular withthe center of axis of the main body case as its center, falls within therange from 13 to 40%. When the filling rate is defined in each of thesezones, good blood flow can be achieved if the difference between thehollow fiber membrane filling rate in the zone lying between theoutermost periphery and a position 1 mm apart from the outermostperiphery and that in the center part is 50% or less.

For the purpose of arranging the fibers in the outermost periphery, amethod in which the hollow fiber membrane bundle is inserted into a caseand is then blown with air from the edge face of the case to scatter thefibers forcibly, a method in which a potting material is injectedthrough a nozzle located on a blood side, and the like is preferablyemployed. As for the shape of the hollow fiber, a crimp structure ispreferred. Specifically, the wave height is preferably 0.1 to 1.5 mm,more preferably 0.1 to 1.0 mm, still more preferably 0.1 to 0.5 mm, andthe wave length is preferably 5 to 30 mm, more preferably 5 to 20 mm,still more preferably 5 to 10 mm.

The term “amplitude” in a crimp of the hollow fiber membrane refers to awidth of a wave of the waving hollow fiber membrane (i.e., half of adistance between the largest value and a smallest value on a y-axis ofone wave (i.e., wave height)). The term “pitch” is also refers to a“wave length”, and refers to a distance between the peak of a wave(i.e., a position at which the width of a wave becomes maximum on ay-axis in one wave length) and the peak of a next wave.

The embodiment according to item [3] mentioned above according to thepresent invention is described with reference to drawings.

FIG. 2 is a vertical cross sectional view that illustrates oneembodiment of a blood treatment apparatus 1 in detail. FIG. 4 is aschematic view that illustrates a zone in which the filling rate is tobe measured in an edge face 31 on a side facing a header for apartitioning wall. FIG. 5 is a schematic view that illustrates the shapeof a crimp formed in the hollow fiber membrane 41.

In FIG. 2, one embodiment of a blood treatment apparatus 1 isillustrated, which is equipped with: a hollow fiber membrane bundle 40which is produced by binding up multiple polysulfone-type hollow fibermembranes and through which blood flows; a main body case 10 in whichthe hollow fiber membrane bundle is stored; partitioning walls 30 and 32which enables the hollow fiber membrane bundle 40 to be held in aliquid-tight state at both ends of the main body case 10 while keepingthe edge faces of the hollow fiber membranes in an opened state; a bloodinlet header 21 which is attached to one end of the main body case 10and through which blood is introduced into the hollow fiber membranebundle 40; and a blood outlet header 23 which is attached to the otherend of the main body case 10 and through which blood is led out.

In the blood treatment apparatus, a dialyzate inlet port 12 is formed atone end of the outer peripheral surface of the main body case 10, adialyzate outlet port 13 is formed at the other end of the outerperipheral surface of the main body case 10, and a baffle 11 which canarrange the flow of a dialyzate is formed immediately beneath each ofthe ports 12 and 13 in such a manner that the baffle 11 extends from thebody part of the main body case 10 and a distance is provided betweenthe tip of the baffle 11 and each of the partitioning walls 30 and 32.The main body case 10 and each of the headers 21 and 23 are joined sothat the headers are pressed against the partitioning wall edge faces 31and 33, thereby forming header internal spaces 27 and 28.

The present inventors have found that the filling rate of the hollowfiber membrane 41 in a zone lying between a position corresponding tothe inner diameter of each of the headers and a position 1 mm apart fromthe aforementioned position toward the inner periphery in thepartitioning wall edge faces 31 and 33 is a critical factor forimproving the occurrence of residual blood in the blood treatmentapparatus. That is, it is found that, if the number of the hollow fibermembrane 41 is small (in other words, if the filling rate of the hollowfiber membrane is low) in the zone, since the amount of blood flowinginto the hollow fiber membrane 41 in the zone is reduced, the flow rateof blood in the outer peripheral parts of the header internal spaces 27and 28 is reduced and the viscosity of blood (which is a non-Newtonianfluid) is increased, resulted in the formation of blood-accumulatedparts. Particularly in a blood treatment apparatus 1 in which thefilling rate of the hollow fiber membrane 41 in each of the partitioningwall edge faces 31 and 33 is lower than that in the body part of themain body case 10, such a tendency is observed remarkably that thereoccurs the uneven distribution in the hollow fiber membrane bundle 40and a zone having a lower filling rate is likely to be formed locally.

Then, in another embodiment of the blood treatment apparatus accordingto the present invention, in each of zones A to H, which are zonesproduced by dividing a zone lying between a position corresponding tothe inner diameter of each of the headers and a position 1 mm apart fromthe aforementioned position toward the inner periphery into equal 8parts equiangular with the center of axis of the main body case as itscenter in each of the edge faces 31 and 33 of each of the partitioningwall 30 and 32 on a side facing each of the headers 21 and 23 as shownin FIG. 4, the filling rate of the hollow fiber membranes is set at 13to 40%. The upper limit of the filling rate of the hollow fibermembranes is preferably 35% or less. The lower limit is preferably 15%or more, more preferably 19% or more. When the filling rate in each ofthe zones A to H is set at 13% or more, the decrease in the flow rate ofblood in the outer peripheral parts of the header internal spaces 27 and28 can be prevented and the occurrence of the accumulation of blood canalso be prevented. If the filling rate is lower than 13%, since bloodcannot flow into the insides of the hollow fiber membrane 41 easily evenif the clearance C between the outer periphery of the hollow fibermembrane bundle 40 and the inner periphery of each of the headers 21 and23 is reduced, blood is likely to be accumulated, resulted in theinduction of the activation of blood and the occurrence of residualblood. If the filling rate excesses 40%, the probability of blocking offthe openings of the hollow fiber membrane 41 by a contact surface 25that contacts with each of the partitioning walls of the headers isincreased.

The hollow fiber membrane filling rate in each of the edge faces 31 and33 of the partitioning walls 30 and 32 on a side facing each of theheaders 21 and 23 can be set as mentioned above in the following manner,for example. Prior to the formation of the partitioning walls 30 and 32,the hollow fiber membrane bundle is inserted into the main body case 10in such a manner that the end parts of the hollow fiber membrane bundleare protruded outside of the main body case 10, and then the end part ofeach of the hollow fiber membranes is sealed. In this regard, it ispreferred that the fiber bundles is arranged by, for example,sandwiching the outer peripheral parts of the protruded parts by opposedtwo plates (referred to as “cover plates”, hereinbelow) each having asemicircular cutout section, so that adjacent hollow fiber membranes cancontact with each other lightly simultaneously with the sealing of thehollow parts. The diameter of the cutout section is determined properly,depending on the inner diameter of the body part of the main body case10 and the header inner diameter. When the diameter of the cutoutsection is slightly smaller than the case inner diameter or the headerinner diameter, adjacent hollow fiber membranes can contact with eachother lightly simultaneously with the sealing of the hollow parts, asmentioned above. If the diameter of the cutout section is smaller thanthe case inner diameter or the header inner diameter and the differencebetween the diameter of the cutout section and each of the case innerdiameter and the header inner diameter is large, it is difficult to setthe filling rate of the hollow fiber membranes in each of the zones A toH at 13% or more.

The hollow fiber membrane bundle 40 is preferably arranged in such amanner that the outer diameter of the hollow fiber membrane bundle 40 isincreased gradually from the tip part of the baffle 11 toward the outerend of the main body case 10. For this purpose, it is preferred toair-blow the edge surface of the hollow fiber membrane bundle. It isalso preferred that, in the edge faces 31, 33 of the partitioning walls30 and 32 on a side opposed to the header, the clearance C between theouter periphery of the hollow fiber membrane bundle 40 and the innerperiphery of each of the headers 21 and 23 becomes 0.3 to 0.6 mm. Bysetting the value of the clearance C at any value falling within theabove-mentioned range, it becomes possible to further reduce theaccumulation of blood in the outer peripheral parts of the headerinternal spaces 27 and 28 and further reduce the possibility of theoccurrence of residual blood while preventing the action of the headers21 and 23 on the openings of the hollow fiber membranes in such a mannerthat the headers 21 and 23 block off the openings of the hollow fibermembranes. The proper range of the clearance C can be selected properlydepending on the shape of the hollow fiber membrane bundle and thefilling rates, and is therefore not limited to the above-mentionedrange.

The ratio of the inner diameter D0 of each of the headers 21 and 23 tothe body part inner diameter D1 of the main body case 10 (i.e., (D0/D1))is preferably 1.05 to 1.25, more preferably 1.15 to 1.25. If the ratiois smaller than 1.05, it becomes difficult for a dialyzate to flow intothe center part of the hollow fiber membrane bundle 40 easily andtherefore bubble removability upon priming tends to be deteriorated.Further, the efficiency of the diffusion of a low-molecular-weightsubstance such as urea from blood into the dialyzate is reducedslightly, and therefore the dialysis performance such as urea clearancetends to be deteriorated. If the ratio is larger than 1.25, it becomesdifficult to keep the hollow fiber membrane filling rate in each of thezones A to H at 13% or more.

Each of the hollow fiber membranes preferably has a crimp structure, asshown in FIG. 5. The preferred ranges for the wave height and the wavelength are as mentioned above. If the wave height is smaller than 0.1mm, it becomes difficult to keep the hollow fiber membrane filling ratein each of the zones A to H at 13% or more, and it also becomesdifficult to form a gap through which the dialyzate flows between thehollow fiber membranes 41, resulted in the deterioration in dialysisperformance. Meanwhile, if the wave height is larger than 1.5 mm, thehollow fiber membrane 41 may be collapsed upon the application ofcrimping to the hollow fiber membrane 41. If the wave length is smallerthan 5 mm, the hollow fiber membrane 41 may be collapsed upon theapplication of crimping to the hollow fiber membrane 41. If the wavelength is larger than 30 mm, it becomes difficult to keep the hollowfiber membrane filling rate in each of the zones A to H at 13% or more,and it also becomes difficult to form a gap through which the dialyzateflows between the hollow fiber membranes 41, resulted in thedeterioration in dialysis performance. The range can be selectedproperly depending on the type or shape of the material for the hollowfiber membrane, and is therefore not limited to the above-mentionedrange.

The hollow fiber membrane filling rate in the body part of the main bodycase 10 is preferably 53 to 64%, more preferably 55% to 62%, still morepreferably 57 to 60%. If the filling rate is smaller than 53%, thedialyzate may undergo short pass and therefore flows into particularsites, resulted in the deterioration in dialysis performance. If thefilling rate is larger than 64%, the hollow fiber membrane 41 may bebroken upon the insertion of the hollow fiber membrane bundle 40 intothe main body case 10.

When the hollow fiber membrane filling rate in each of the zones A to His set at 13% or more, the difference between the average value of thehollow fiber membrane filling rates in the zones A to H and the hollowfiber membrane filling rate in the body part is preferably 50% or less,preferably 40% or less, from the viewpoint of the prevention of thedisruption of the flow of blood.

With respect to the joint of the headers 21 and 23 to the main body case10, it is desirable that each of the headers 21 and 23 and the main bodycase 10 are attached to each other and the headers 21 and 23 are broughtinto contact with and pressed against the partitioning wall edge faces31 and 33, respectively, to secure sealing properties, from theviewpoint of the prevention of the accumulation of blood. In thisregard, a ring-shaped elastic body made from a silicon rubber or thelike may be provided to the header so that the ring-shaped elastic bodycan be in contact with each of the partitioning wall edge faces 31 and33 to thereby secure sealing properties. In this case, it is preferredto reduce the size of a space formed by the ring-shaped elastic body aspossible, from the viewpoint of the reduction of blood-accumulatedparts.

The shape of the ring-shaped elastic body is properly selected in such amanner that the elastic body does not block off the hollow openings ofthe hollow fiber membranes, with the amount of deformation of theelastic body caused by pressurization, the changes in sizes of the mainbody case 10 and the headers 21 and 23, the accuracy of assembly of themodule and the like taken into consideration. As for the joining method,ultrasonic welding, the joining with a solvent, spin welding, fittingwith screws and the like may be employed. Among these, ultrasonicwelding is preferred, since high productivity can be achieved andsealing properties can be secured even at joint parts.

The baffle 11 may be a tongue-shaped baffle that does not reach theabove-mentioned partitioning walls 30 and 32, multiple tongue-shapedbaffles, a ring-shaped baffle, a ring-shaped baffle having slits formedtherein, or a baffle of which the tip reaches the partitioning walls 30and 32.

The materials for the main body case 10 and the headers 21 and 23 arenot particularly limited, and polystyrene, polycarbonate, polymethylmethacrylate, polyethylene, polypropylene and the like can be usedsuitably.

When an embodiment in which a hydrophilic copolymerization polymerhaving a relaxation time of adsorbed water of 2.5×10⁻⁸ seconds orshorter and 5.0×10⁻¹⁰ or longer at −40° C. is present on theblood-contacting surface of each of the hollow fiber membranes iscombined, the effect of the embodiment of item [3] can become maximum.Therefore, as mentioned in Examples and Comparative Examples below, ifthe hydrophilic copolymerization polymer is not used, the effect cannotbecome maximum. That is, when a technique using the hydrophiliccopolymerization polymer or the like to improve the blood flow in thecenter part of the module cross section, it is highly required to carethe blood flow in the outermost peripheral part in the cross section andtherefore it is considered that the application of this technique canprovide a drastic effect.

Further, when particulate protuberances each having a particle diameter50 nm or more are present on the blood-contacting surface of each of thehollow fiber membranes at a density of more than 3 particles/μm², theeffect of the optimization of the distribution of the hollow fibermembranes is not sometimes developed. In this case, it is consideredthat, although the blood flow is improved, the need of optimizing theblood flow in the outermost peripheral part is increased.

With respect to the headers 21 and 23, if the surface unevenness ishigh, the activation of blood can be induced, leading to the occurrenceof residual blood. Therefore, the roughness (Ra) of the header innersurface is preferably 0.8 μm or less, more preferably 0.5 μm or less,still more preferably 0.3 μm or less. Similarly, the roughness (Ra) ofthe edge face is preferably 1 μm or less, more preferably 0.5 μm orless, still more preferably 0.3 μm or less.

In addition, the inner diameter of the hollow fiber membrane ispreferably 100 to 400 μm, more preferably 120 to 250 μm, still morepreferably 140 to 200 μm. The thickness of the membrane is preferably 10to 100 μm, more preferably 20 to 70 μm, still more preferably 30 to 50μm.

For the purpose of preventing the occurrence of residual blood in anartificial kidney, the hollow fiber membrane module preferably has thefollowing property: when 2 L of bovine blood having a temperature of 37°C., having a hematocrit value of 30%, the total protein concentration of6.5 g/dL and a β₂-microglobulin (β₂-MG) concentration of 1 mg/L, andcontaining sodium citrate is allowed to flow through the hollow fibermembrane module at a flow rate of 200 mL/min and a filtration flow rateof 16 mL/min, the ratio of the sieving coefficient of albumin after 5minutes (Sc-Alb(5)) to that after 20 minutes (Sc-Alb(20)) (i.e., (Sc-Alb(20)/Sc-Alb (5)) is preferably 0.5 to 1.0, more preferably 0.7 to 0.95,and the ratio of the sieving coefficient of β₂-MG after 5 minutes tothat after 20 minutes (i.e., (Sc-β₂MG (20)/sc-β₂MG(5)) is 1.01 to 1.20,preferably 1.05 to 1.15. With respect to the overall mass transfercoefficient for urea, the ratio of that in an aqueous system (Ko(W)) tothat in a bovine plasma system (Ko(B)) (i.e., (Ko(B)/Ko(W))) ispreferably 0.8 or more, more preferably 0.85 or more.

A fact that the Sc-Alb(20)/Sc-Alb(5) value is less than 1 means that aprotein or the like is deposited onto the membrane over time andtherefore the number or size of pores through which albumin can pass isreduced. In contrast, a fact that the Sc-β₂MG(20)/Sc-β₂MG(5) value islarger than 1 means that β₂-MG is entrapped by the membranes. Thedifference between these facts is due to the difference in molecularweights of these substances. That is, it is considered that: albumin hasa molecular weight of about 6.6000 and the pore sizes of the membraneare so controlled that albumin cannot pass therethrough; on the otherhand, β₂-MG has a molecular weight of about 1.2000, and the pore sizesof the membrane are so controlled that β₂-MG can path therethrough, andβ₂-MG is trapped in the inside of the membrane.

A fact that the difference in overall mass transfer coefficient for ureais small between an aqueous system and a bovine plasma system means thatthe stimulation applied to blood cells during blood dialysis therapy maybe small, which suggests that the surface configuration of the membraneduring the contact of the membrane with water is the same as that duringthe contact of the membrane with blood. After the dialysis therapy iscompleted, for returning blood in the separation membrane module intothe body, a saline solution is allowed to pass through the membranemodule. It is assumed that the alteration in configuration of thesurface of the membrane caused by a saline solution may affect thetendency of the occurrence of residual blood. However, it is consideredthat the use of the hollow fiber membrane according to the presentinvention rarely causes the alteration in configuration of the surfaceof the membrane.

The overall mass transfer coefficient for urea can be calculated bymeasuring a urea clearance. For the measurement of the urea clearance, ahollow fiber membrane module having a surface area of 1.6 m² ispreferably used. If it is difficult to produce a 1.6 m² hollow fibermembrane module, a separation membrane module having a surface areaclose to the above-mentioned value as possible is used for themeasurement of the clearance.

The measurement method for urea clearance in an aqueous system iscarried out in accordance with dialyzer performance evaluation criteriaedited by Japan Society for Artificial Organs (issued on September,1982). In the criteria, there are mentioned two types of measurementmethods. In the present invention, the experiments are carried outemploying TMP 0 mmHg as a reference.

The details of the method for measuring urea clearance in bovine plasmaare mentioned below. In the case of an artificial kidney, the followingconditions are employed: the blood side flow rate is 200 mL/min, thedialyzate side flow rate is 500 mL/min, and the filtration flow rate is10 mL/min/m². The total protein concentration is 6.5±0.5 g/dL and theurea concentration is 1 g/L.

From the viewpoint of removal performance, the value of the aqueous ureaclearance is preferably 180 mL/min or more, more preferably 190 mL/minor more, still more preferably 195 mL/min or more.

The water permeation performance of the hollow fiber membrane module ispreferably 200 mL/hr/m²/mmHg or more, more preferably 300 mL/hr/m²/mmHgor more, still more preferably 400 mL/hr/m²/mmHg or more. If the waterpermeation performance is too high, although internal filtration mayoccur and the solute removal performance is increased, stimuli on bloodcells are also increased. Therefore, the water permeation performance ispreferably 2000 mL/hr/m²/mmHg or less, more preferably 1500mL/hr/m²/mmHg or less, still more preferably 1000 mL/hr/m²/mmHg or less.The water permeation performance (UFR) can be calculated in accordancewith the following formula:

UFR(mL/hr/m²/mmHg)=Q _(w)/(P×T×A)

(wherein Q_(W): amount of filtration (mL), T: ef flux time (hr), P:pressure (mmHg), A: inner surface area of the hollow fiber membrane(m²))

The present invention is described with reference to examples, but thepresent invention is not limited to these examples.

EXAMPLES (1) Observation of Inner Surface on SEM

A hollow fiber membrane was sliced into a semi-cylindrical shape with asingle-edged knife so that the inner surface of the hollow fibermembrane was exposed. Subsequently, a Pt—Pd thin film was formed on thesurface of the hollow fiber membrane by sputtering, thereby producing asample. The inner surface of the hollow fiber membrane sample wasobserved on a field emission-type scanning electron microscope (S800manufactured by Hitachi, Ltd.)

at a magnification of 50,000 times, and the number of particulateprotuberances each having a particle diameter of 50 nm or more in anarbitrary 1 μm² area was counted.

(2) Measurement of Relaxation Time

In the invention of the present application, dielectric relaxationspectra obtained by a TDR (Time Domain Reflectometly) method and an IMA(Impedance Material Analyzer) method were fitted using the formulaeshown below to determine a relaxation time.

$\begin{matrix}{ɛ^{*} = {{ɛ^{\prime} + {\; ɛ^{''}}} = {ɛ_{\infty} + {\sum\limits_{n}\frac{\Delta \; ɛ_{n}}{1 + \left( {\; 2\; \pi \; f\; \tau_{n}} \right)^{\beta_{n}}}} + {\sum\limits_{m}{\Delta \; ɛ_{m}{\int_{0}^{\infty}{\left( {- \ \frac{\Phi_{m}}{t}} \right){\exp \left( {{- }\; 2\; \pi \; f\; t} \right)}{t}}}}} - {\frac{\sigma}{2\; \pi \; f\; ɛ_{0}}}}}} & \left\lbrack {{Formula}\mspace{14mu} 1} \right\rbrack\end{matrix}$

wherein

φm=exp(−(t/τm)^(β) m)  [Formula 2]

wherein∈*: a complex dielectric constant, ∈′: a substantial part of a complexdielectric constant (dielectric constant), ∈″: an imaginary part of acomplex dielectric constant (dielectric loss), ∈∞: a dielectric constantwhen the frequency is infinite, Δ∈: a relaxation strength, τ: arelaxation time, β: a parameter representing the width of distributionof relaxation (0<β≦1), f: a frequency, t: a time, σ: an electricalconductivity, and ∈0: a dielectric constant of vacuum.

In the IMA method, an RF impedance/material analyzer 4291B(Hewlett-Packard) was used, wherein the frequency was 1 MHz to 500 MHz.

In the TDR method, an oscilloscope HP54120B (Hewlett-Packard) was used,wherein the frequency was 500 MHz to 20 GHz.

The measurement sample used was an aqueous 40 wt % solution (pure waterwas used). The sample was set in the device, and the measurement wascarried out after cooling the sample to −40° C. and then allowing thesample to stand for about 1 hour. Since bulk water was frozen andtherefore the dielectric relaxation was not observed, bulk water couldbe distinguished from adsorbed water. Water adsorbed onto a polymer isexpressed as a peak in which f is observed around 10⁻⁹ to 10⁻¹⁰ when ∈″and f are plotted.

(3) X-Ray Photoelectron Spectrometry (XPS) Measurement

The hollow fiber membrane was sliced into a semi-cylindrical shape witha single-edged knife, and the measurement was performed at arbitrarythree points in each of the inner surface and the outer surface of thehollow fiber membrane in the manner mentioned below. The measurementsample was rinsed with ultrapure water, then dried at room temperatureat 0.5 Torr for 10 hours and then subjected to the measurement. Thefollowing analyzer and conditions were used.

Analyzer: ESCA LAB220iXL

Excitation X-ray: monochromatic Al Kα1,2 radiation (1486.6 eV)X-ray diameter: 0.15 mmPhotoelectron escape angle: 90° (the tilt of the detector relative tothe sample surface).

(4) Measurement of Surface Unevenness

A center line average roughness (Ra) was measured using a contact-typesurface roughness meter.

(5) Measurement of Hollow Fiber Membrane Filling Rate

A blood inlet header 21 and a blood outlet header 23 were removed from ablood treatment apparatus 1, the blood treatment apparatus 1 was placedwith a dialyzate inlet port 12 and a dialyzate outlet port 13 of a mainbody case 10 facing down, each of partitioning wall edge faces 31 and 33was irradiated with ultraviolet ray from an ultraviolet ray irradiationdevice, and an image of each of the partitioning wall edge faces 31 and33 was taken. As a light source for ultraviolet ray, a mercury xenonlamp having a center wavelength for irradiated ultraviolet ray of 365 nmwas used. As a light guide for the ultraviolet ray irradiation device, aquartz-made optical fiber light guide was used. The shape of the lightguide for the ultraviolet ray irradiation device was circular, the angleof irradiation with ultraviolet ray was 60 degrees, the output ofultraviolet ray was 150 W, and the position at which the device was tobe set was so adapted that the center of an edge face of the bloodtreatment apparatus aligned with the center of the light guide and wasset at a position 20 mm apart from the edge face of the blood treatmentapparatus. As an imaging device, a 7450-pixel line sensor camera wasused, and a lens having permeability of light having a wavelength of 200nm to 450 nm of 70% or more and having a focal length of 105 mm wasselected so that 1 pixel corresponds to 7 on the edge face of the bloodtreatment apparatus. The camera was placed at the front of the bloodtreatment apparatus so that the optical center of the lens aligned withthe centers of the blood treatment apparatus and the light guide.

In each of images obtained, outlines of the hollow fiber membranes andoutlines of other parts were highlighted by means for a bypass filter.Each of the resulting images was subjected to a binary coded processingat a predetermined threshold value, so that the parts of the hollowfiber membranes had lighter brightness values and other parts had darkerbrightness values. The threshold value employed was determined bymultiplying an average brightness value for an imaged 10 mm square areathat was concentric with the centers of the partitioning wall edge faces31 and 33 by 0.7. Subsequently, inner diameter parts (regions eachhaving a darker brightness value and surrounded by and separated fromthe regions each having a brighter brightness value) were identified bya known particle analysis technique, and a center coordinate for theinner diameter part of each of the hollow fiber membranes, for which thecenter of the partitioning wall edge face 31 or the partitioning walledge face 33 was employed as the origin, was determined. Further, asshown in FIG. 4, a zone lying between a position corresponding to theinner diameter of each of the headers and a position 1 mm apart from theaforementioned position toward the inner periphery was divided at 45°intervals into equal 8 parts with the origin as its center to producezones A to H, subsequently the number of the hollow fiber membranes 41each having a center coordinate of the inner diameter part thereof ineach of the zones A to H was counted, and the filling rate wascalculated from the formula shown below. As the outer diameter of eachof the hollow fiber membranes, the header inner diameter D0, and thebody part inner diameter D1 of the main body case, designed values wereemployed.

$\begin{matrix}{{{Filling}\mspace{14mu} {rate}\mspace{14mu} {in}\mspace{14mu} {each}\mspace{14mu} {zone}\mspace{14mu} (\%)} = {\frac{\begin{matrix}{8 \times \left( {{outer}\mspace{14mu} {diameter}\mspace{14mu} {of}\mspace{14mu} {hollow}\mspace{14mu} {fiber}\mspace{14mu} {membrane}} \right)^{2} \times} \\\left( \begin{matrix}{{number}\mspace{14mu} {of}\mspace{14mu} {hollow}\mspace{14mu} {fiber}\mspace{14mu} {membranes}} \\{{present}\mspace{14mu} {in}\mspace{14mu} {each}\mspace{14mu} {zone}}\end{matrix}\mspace{14mu} \right)\end{matrix}}{\begin{pmatrix}{\left( {{inner}\mspace{14mu} {diameter}\mspace{14mu} D\; 0\mspace{14mu} {of}\mspace{14mu} {header}} \right)^{2} -} \\\left\lbrack {\left( {{inner}\mspace{14mu} {diameter}\mspace{14mu} D\; 0\mspace{14mu} {of}\mspace{14mu} {header}} \right) - 2} \right\rbrack^{2}\end{pmatrix}} \times 100}} & {\left\lbrack {{Formula}\mspace{14mu} 3} \right\rbrack \mspace{11mu}} \\{{{Filling}\mspace{14mu} {rate}\mspace{14mu} {in}\mspace{14mu} {body}\mspace{14mu} {part}\mspace{14mu} (\%)} = {\frac{\begin{matrix}{\left( {{outer}\mspace{14mu} {diameter}\mspace{14mu} {of}\mspace{14mu} {hollow}\mspace{14mu} {fiber}\mspace{14mu} {membrane}} \right)^{2} \times} \\\left( \begin{matrix}{{total}\mspace{14mu} {number}\mspace{14mu} {of}\mspace{14mu} {hollow}\mspace{14mu} {fiber}} \\{{membranes}\mspace{14mu} {in}\mspace{14mu} {blood}\mspace{14mu} {treatment}\mspace{14mu} {apparatus}}\end{matrix}\mspace{14mu} \right)\end{matrix}}{\begin{pmatrix}{{inner}\mspace{14mu} {diameter}\mspace{14mu} D\; 1\mspace{14mu} {of}\mspace{14mu} {body}} \\{{part}\mspace{14mu} {of}\mspace{14mu} {main}\mspace{14mu} {body}\mspace{14mu} {case}}\end{pmatrix}^{2}} \times 100}} & \left\lbrack {{Formula}\mspace{14mu} 4} \right\rbrack\end{matrix}$

(6) Crimp Measurement Method

The pitch and amplitude of a crimp applied to each of the hollow fibermembranes 41 were measured in the following manner. First, both endparts of the main body case 10 of the blood treatment apparatus were cutin a direction vertical to the axis direction at positions each of whichwas located inside of a partitioning wall as observed in an axisdirection. One end of the drawn hollow fiber membrane was fixed, and aload of 1 g was applied to the other end, so that the hollow fibermembrane was allowed to swing down in a vertical direction. The numberof wave tops was counted sequentially with starting from an arbitralwave top toward the x-direction, wherein x-axis was the downwarddirection and y-axis was the rightward direction as observed by anobserver. The x-direction distance until the count number became 10 wasmeasured, and one tenth of the direction was defined as the pitch. Thewave width in an arbitrary wave top and the wave width in a wave bottomthat was nearest from the aforementioned peak top as observed in thex-direction (i.e., a position at which the wave width became minimum inone wave length as observed in the y-direction in one wave length) weremeasured using a microscope, and one-half of the distance between thewave top and the wave bottom was calculated. The measurement was carriedout at different 10 positions, and an average of calculated values forthe 10 positions was defined as an amplitude.

(7) Test on the Occurrence of Residual Blood

A blood treatment apparatus 1 was washed with a saline solution byallowing 700 mL in total of a saline solution to flow at a flow rate of200 mL/min from the blood side with the blood inlet header 21 facingdown. In this procedure, no bubble removal operation (e.g. theapplication of vibrations to the blood treatment apparatus 1) wascarried out.

Subsequently, a dialyzate was allowed to flow from the dialyzate side ata flow rate of 500 mL/min, and bovine blood was introduced into theblood side at 100 mL/min. In this manner, dialysis was started. Thebovine blood used was added with heparin, and was so prepared as to havea hematocrit value of 30% and the total protein amount of 6.5 g/dL.After it was confirmed that the bovine blood appeared at the bloodoutlet header 23 through the hollow fiber membranes, the flow rate wasaltered to 200 mL/min and the blood treatment apparatus 1 was reversedup-and-down so that the blood flowed from the top to the bottom. Theblood was allowed flow for 5 minutes while keeping this state. The waterremoval amount was 0. The returned blood was washed with a salinesolution by allowing 300 mL in total of the saline solution to flow fromthe top to the bottom at a flow rate of 100 mL/min. Subsequently, thenumber of hollow fiber membranes 41 which were remained in the bloodtreatment apparatus 1 and in which the blood was remained was counted.The bovine blood was not fresh blood, and therefore the function ofplatelets was decreased. Therefore, for the evaluation ofanti-thrombotic properties of a material, it is necessary to evaluatethe material with respect to both this test and the evaluation on thedeposition of platelets to the material as mentioned in item (11) below.

(8) Measurement of Sieving Coefficient

Bovine blood (heparin-treated blood) that was kept warm at a temperatureof 37° C. and had a hematocrit value 30%, and the total protein amountof 6.5 g/dL was used in a blood tank, and the bovine blood was fed tothe inside of the hollow fiber using a pump at a flow rate of 200mL/min. In this test, the pressure on the module outlet side was socontrolled that the filtration amount became 10 mL/min per 1 m² (i.e.,16 mL/min for 1.6 m²), and a filtrate and the blood at the outlet werereturned to the blood tank. Five minutes and twenty minutes after theinitiation of reflux, the blood at an inlet and an outlet on the hollowfiber side and the filtrate were sampled. The blood was centrifuged intoserum and then analyzed using a BCG (bromocresol green) method kit(tradename: A/GB Test Wako (Wako Pure Chemical Industries, Ltd.)), thealbumin permeability (%) was calculated from the concentration. In thecalculation of the concentration of the filtrate, with respect to thecalibration curve for albumin, for the purpose of obtaining goodsensitivity and producing a calibration curve at low concentrations,serum albumin included in the kit was diluted properly for theproduction of the calibration curve.

The sieving coefficient was calculated from concentrations of eachsolution in accordance with the following formula.

Sieving coefficient(Sc)=CF/(CBi/2+CBo/2)×100

In the formula, CF: the concentration of a solute in an F solution, CBi:the concentration of a solute in a Bi solution, and CBo: theconcentration of a solute in a Bo solution.

(9) Measurement of Urea Performance in Aqueous System

An experiment was carried out in accordance with dialyzer performanceevaluation criteria edited by Japan Society for Artificial Organs(issued on September, 1982). In the criteria, there are mentioned twotypes of measurement methods. In the experiment, TMP 0 mmHg was employedas a reference. The clearance (C_(L)) was calculated in accordance withthe following formula.

C _(L)(mL/min)={(CBi−Bo)/CBi}×Q _(B)

In the formula, CBi: the concentration of urea at an inlet side of themodule, CBo: the concentration of urea at an outlet side of the module;and Q_(B): the flow rate on the blood side (mL/min).

The overall mass transfer coefficient (Ko) can be calculated from theclearance in accordance with the following formula.

$\begin{matrix}{{Ko} = {\frac{Q_{B}}{A\left( {1 - {Q_{B}/Q_{D}}} \right)}{\ln \left( \frac{1 - {C_{L}/Q_{D}}}{1 - {C_{L}/Q_{B}}} \right)}}} & \left\lbrack {{Formula}\mspace{14mu} 5} \right\rbrack\end{matrix}$

In the formula, Ko: an overall mass transfer coefficient (cm/min), A: asurface area (cm²) of a membrane, and Q_(D): the flow rate of adialyzate (mL/min).

(10) Measurement of Urea and β₂-MG Performance in Bovine Plasma System

Bovine blood having disodium ethylenediaminetetraacetate added theretowas so prepared as to have a hematocrit value of 30% and a total proteinamount of 6.5 g/dL.

Subsequently, urea and β₂-MG were added to the bovine blood so that theurea concentration became 1 g/L and the β₂-MG concentration became 1mg/L, and the resulting mixture was agitated. The resulting bovine bloodwas divided into a 2 L aliquot for circulation and a 1.5 L aliquot forclearance measurement.

A circuit was assembled as shown in FIG. 6, and a hollow fiber membranemodule was set in the circuit. TR2000S manufactured by TORAY MEDICALCO., LTD. was used as a dialyzer. In FIG. 6, TR2000S corresponds to theBi pump, the F pump, and the dialyzer.

Dialyzate solutions A and B (Kindaly solution AF No. 2 manufactured byFuso Pharmaceutical Industries, Ltd.) were placed in the dialyzer. ROwater was allowed to flow from the dialyzate side to the blood side. Thedialyzate concentration, the temperature, and the dialyzate side flowrate (Q_(D)) were set at 13-15 mS/cm, 34° C. or higher, and 500mL/minute, respectively.

The water removal rate (Q_(F)) of the dialyzer was set at 10mL/(min·m²). The inlet of the Bi circuit was placed in a circulationbeaker containing 2 L of the bovine blood (37° C.) prepared as mentionedabove, and the Bi pump was started. After the liquid from the outlet ofthe Bo circuit was discarded for 90 seconds, the outlet of the Bocircuit and the outlet of the Do circuit were immediately placed incirculation beakers to form a circulation state. The blood side flowrate (Q_(B)) was set at 200 mL/min.

Subsequently, the F pump of the dialyzer was started to operate. Afterthe circulation was performed for 1 hour, the Bi and F pumps werestopped.

The inlet of the Bi circuit was then placed in the bovine blood preparedas mentioned above for clearance measurement, and the outlet of the Bocircuit was placed in a beaker for discharge. The liquid from the outletof the Do circuit was discarded.

The Di pump was started. The blood pump was also started, and the spacebetween the trap and the Bi chamber was opened (Q_(B) 200 mL/min, Q_(D)500 mL/min, Q_(F) 10 mL/(min·m²)).

Two minutes after the start, 10 mL of a sample was collected from thebovine blood (37° C.) for clearance measurement and defined as Biliquid. Four minutes and 30 seconds after the start, 10 mL of a samplewas collected from the outlet of the Bo circuit and defined as Boliquid. These samples were stored in a freezer at −20° C. or lower.

A clearance was calculated from the concentration of each solution inthe same manner as mentioned above. With respect to urea, the overallmass transfer coefficient was determined.

(11) Method for Testing Deposition of Human Platelets on Hollow FiberMembrane

A double-side tape was bonded to an 18 mmφ polystyrene circular plate,and the hollow fiber membrane was fixed thereon. The bonded hollow fibermembrane was sliced into a semi-cylindrical shape with a single-edgedknife so that the inner surface of the hollow fiber membrane wasexposed. It should be carefully performed, because if there is dirt, ascratch, a fold, or the like on the inner surface of the hollow fiber,platelets may be deposited on such a portion so that the evaluation maynot be correctly performed. The circular plate was bonded to acylindrical cut piece of Falcon (registered trademark) tube (No. 2051,18 mmφ) so that the hollow fiber membrane-carrying surface was placedinside the cylinder, and the gap was filled with Parafilm. The interiorof the cylindrical tube was washed with a saline solution and thenfilled with a saline solution. Heparin was added at a concentration of50 U/mL to human venous blood immediately after the blood sampling.After the saline solution was discharged from the cylindrical tube, 1.0mL of the blood was placed in the cylindrical tube within 10 minutesafter the sampling and shaken at 37° C. for 1 hour. Thereafter, thehollow fiber membrane was washed with 10 mL of a saline solution, andthe blood component was fixed thereon with a 2.5% by volumeglutaraldehyde saline solution and washed with 20 mL of distilled water.The washed hollow fiber membrane was dried at room temperature under areduced pressure of 0.5 Torr for 10 hours. The hollow fiber membrane wasthen bonded to the sample stage of a scanning electron microscope with adouble-side tape. A Pt—Pd thin film was then formed on the surface ofthe hollow fiber membrane by sputtering, thereby producing a sample. Theinner surface of the hollow fiber membrane was observed on a fieldemission-type scanning electron microscope (S800 manufactured byHitachi, Ltd.) at a magnification of 1,500 times, and the number of thedeposited platelets per field (4.3×10³ μm²) was counted. The number ofthe deposited platelets (/4.3×10³ μm²) was defined as the average of thenumbers of the deposited platelets which were counted in ten differentfields at and around the longitudinal center of the hollow fiber. Whenthe number of the deposited platelets per field exceeded 100 (/4.3×10³),the result was counted as 100. The longitudinal ends of the hollow fiberwere omitted from the objects to be measured for the number of deposits,because blood tended to stay thereon. The number of the depositedplatelets is preferably 20(/(4.3×10³ μm²)) or less.

(12) Measurement of Flexible Layer on the Inner Surface of Hollow FiberMembrane

The hollow fiber membrane was sliced into a semi-cylindrical shape witha single-edged knife, and the inner surface was measured on an atomicforce microscope (AFM). The measurement sample was rinsed with ultrapurewater, then dried at room temperature at 0.5 Torr for 10 hours, and thenused for the measurement.

The hollow fiber membrane was attached onto a sample stage, waterdroplets were dropped over the membrane to moisten the membrane, therebymaking the membrane in a moistened state having a water content of 65%by weight or more. In this state, a force curve measurement was carriedout in a contact mode. A careful attention was paid so as not to dry thesurface of the sample during the measurement. When a flexible layer ispresent on the surface in the approach of a cantilever to the sample, acurved part can be observed. The distance of the curved part was definedas a flexible layer. The measurement was carried out at 20 parts, and anaverage value of the results was used. With respect to the average valueemployed, the first decimal place of the average value was rounded off.

The AFM observation conditions were as follows: a scanning probemicroscope SPM 9500-J3 (SHIMADZU, Kyoto, Japan) was used as anapparatus, the observation mode was a contact mode, the probe used wasNP-S (120 mm, wide) (Nihon VEECO KK, Tokyo, Japan), the scanning rangewas 5 μm×5 μm, and the scanning speed was 1 Hz.

(Production of Hollow Fiber Membrane 1-1)

Sixteen parts by weight of polysulfone (Udel-P3500, Amoco), 2 parts byweight of PVP (K90, ISP) and 4 parts by weight of PVP (K30, ISP) weredissolved by heating at 90° C. for 10 hours together with 77 parts byweight of DMAc and 1 part by weight of water while agitating with animpeller at 50 rpm, thereby preparing a membrane forming stock solution.The stock solution was stored at 60° C. for 48 hours and then spun.

The membrane forming stock solution was fed to a spinning nozzle at atemperature of 50° C. and then ejected through a double annular slittube having a circular slit section with an outer diameter of 0.35 mmand an inner diameter of 0.25 mm, and a solution comprising 65 parts byweight of DMAc and 35 parts by weight of water was ejected through anintercircular section as a core injection solution (hereinbelow, alsoreferred to as “injection solution” for convenience). After theformation of a hollow fiber membrane, the hollow fiber membrane wasallowed to pass through a 350 mm dry-zone atmosphere at a temperature of30° C. and a relative humidity of 75% RH and then through a coagulationbath of 14% by weight of DMAc and 86% by weight of water at atemperature of 40° C. The hollow fiber membrane was then subjected to awater washing process at 85° C. for 120 seconds, a drying process at130° C. for 2 minutes, and a crimping process. The resulting hollowfiber membrane 1-1 was wound into a bundle. The hollow fiber membraneimmediately before the drying step had a tensile force of 67 g/mm². Thehollow fiber membrane had an inner diameter of 195 μm and a thickness of40 μm. The shape of a crimp was determined, and it was found that thecrimp had a wave height of 0.3 mm (amplitude: 0.15 mm) and a wave length(pitch) of 8.0 mm.

(Production of Hollow Fiber Membrane 1-2)

Spinning was carried out under the same conditions as employed for theproduction of the hollow fiber membrane 1-1. The resulting hollow fibermembrane had an inner diameter of 200 μm and a thickness of 40 μm. Theshape of a crimp was determined, and it was found that the crimp had awave height of 0.2 mm (amplitude: 0.1 mm) and a wave length (pitch) of8.0 mm.

(Production of Hollow Fiber Membrane 2-1)

Sixteen parts by weight of polysulfone (Udel-P3500, Amoco), 2 parts byweight of PVP (K90, ISP) and 4 parts by weight of PVP (K30, ISP) weredissolved by heating at 80° C. for 10 hours together with 77 parts byweight of DMAc and 1 part by weight of water while agitating with animpeller at 50 rpm, thereby preparing a membrane forming stock solution.The stock solution was stored at 60° C. for 48 hours and then spun.

The membrane forming stock solution was fed to a spinning nozzle at atemperature of 50° C. and then ejected through a double annular slittube having a circular slit section with an outer diameter of 0.35 mmand an inner diameter of 0.25 mm, and a solution prepared by dissolving10 parts by weight of a vinylpyrrolidone-vinyl acetate copolymerizationpolymer (60/40 (by weight)) in a solution comprising 63 parts by weightof DMAc and 37 parts by weight of water was ejected through anintercircular section as a core injection solution. After the formationof a hollow fiber membrane, the hollow fiber membrane was allowed topass through a 350 mm dry-zone atmosphere at a temperature of 28° C. anda relative humidity of 95% RH and then through a coagulation bath of 14%by weight of DMAc and 86% by weight of water at a temperature of 40° C.The hollow fiber membrane was then subjected to a water washing processat 80° C. for 120 seconds, a drying process at 130° C. for 2 minutes,and a crimping process. The resulting hollow fiber membrane (2) waswound into a bundle. The hollow fiber membrane immediately before thedrying step had a tensile force of 113 g/mm². The hollow fiber membranehad an inner diameter of 185 μm and a thickness of 38 μm. The shape of acrimp was determined, and it was found that the crimp had a wave heightof 0.4 mm (amplitude: 0.2 mm) and a wave length (pitch) of 8.0 mm.

(Production of Hollow Fiber Membrane 2-2)

Spinning was carried out under the same conditions employed for theproduction of the hollow fiber membrane 2-1. The resulting hollow fibermembrane had an inner diameter of 200 μm and a thickness of 40 μm. Theshape of a crimp was determined, and it was found that the crimp had awave height of 0.2 mm (amplitude: 0.1 mm) and a wave length (pitch) of8.0 mm.

(Production of Hollow Fiber Membrane 2-3)

Spinning was carried out under the same conditions employed for theproduction of the hollow fiber membrane 2-1. The resulting hollow fibermembrane had an inner diameter of 200 μm and a thickness of 40 μm. Theshape of a crimp was determined, and it was found that the crimp had awave height of 1.7 mm (amplitude: 0.85 mm) and a wave length (pitch) of17 mm.

(Production of Hollow Fiber Membrane 3)

Eighteen % by weight of polysulfone (Udel-P3500, Amoco) and 9% by weightof a vinylpyrrolidone-vinyl acetate copolymerization polymer (60/40 (byweight)) were dissolved by heating at 90° C. for 10 hours together with72% by weight of DMAc and 1% by weight of water while agitating with animpeller at 50 rpm, thereby preparing a membrane forming stock solution.The stock solution was stored at 60° C. for 48 hours and then spun.

The membrane forming stock solution was fed to a spinning nozzle at atemperature of 45° C. and then ejected through a double annular slittube having a circular slit section with an outer diameter of 0.35 mmand an inner diameter of 0.25 mm, and a solution comprising 60% byweight of DMAc and 40% by weight of water was ejected through anintercircular section as a core injection solution. After the formationof a hollow fiber membrane, the hollow fiber membrane was allowed topass through a 350 mm dry-zone atmosphere at a temperature of 30° C. anda relative humidity of 70% RH and then through a coagulation bath of 14%by weight of DMAc and 86% by weight of water at a temperature of 40° C.The hollow fiber membrane was then subjected to a water washing processat 80° C. for 120 seconds, a drying process at 130° C. for 2 minutes,and a crimping process. The resulting hollow fiber membrane (3) waswound into a bundle. The hollow fiber membrane immediately before thedrying step had a tensile force of 33 g/mm². The hollow fiber membranehad an inner diameter of 200 μm and a thickness of 40 μm. The shape of acrimp was determined, and it was found that the crimp had a wave heightof 0.3 mm (amplitude: 0.15 mm) and a wave length (pitch) of 7.0 mm.

(Production of Hollow Fiber Membrane 4)

Seventeen parts by weight of polysulfone (Udel-P3500, Amoco) and 5 partsby weight of PVP (K90, ISP) were dissolved by heating at 50° C. for 48hours together with 77 parts by weight of DMAc and 1 part by weight ofwater while agitating with an impeller at 10 rpm, thereby preparing amembrane forming stock solution. The stock solution was stored at 55° C.for 48 hours and then spun.

The membrane forming stock solution was fed to a spinning nozzle at atemperature of 70° C. and then ejected through a double annular slittube having a circular slit section with an outer diameter of 0.35 mmand an inner diameter of 0.25 mm, and a solution comprising 57 parts byweight of DMAc and 43 parts by weight of water was ejected as a coreinjection solution. After the formation of a hollow fiber membrane, thehollow fiber membrane was allowed to pass through a 350 mm dry-zoneatmosphere at a temperature of 55° C. and a relative humidity of 75% RHand then through a coagulation bath of 14% by weight of DMAc and 86% byweight of water at a temperature of 65° C. The hollow fiber membrane wasthen subjected to a water washing process at 85° C. for 120 seconds tobundle together, a drying process at 80° C. for 7 hours, and a crimpingprocess. The resulting hollow fiber membrane (4) was wound into abundle. The hollow fiber membrane had an inner diameter of 190 μm and athickness of 45 μm. The shape of a crimp was determined, and it wasfound that the crimp had a wave height of 0.3 mm (amplitude: 0.15 mm)and a wave length (pitch) of 8.0 mm.

(Production of Hollow Fiber Membrane 5)

Eighteen % by weight of polysulfone (Udel-P3500, Amoco) was dissolved byheating at 90° C. for 10 hours together with 81% by weight of DMAc and1% by weight of water while agitating with an impeller at 50 rpm,thereby preparing a membrane forming stock solution. The stock solutionwas stored at 60° C. for 48 hours and then spun.

The membrane forming stock solution was fed to a spinning nozzle at atemperature of 50° C. and then ejected through a double annular slittube having a circular slit section with an outer diameter of 0.35 mmand an inner diameter of 0.25 mm, and a solution comprising 63% byweight of DMAc and 37% by weight of water was ejected through anintercircular section as a core injection solution. After the formationof a hollow fiber membrane, the hollow fiber membrane was allowed topass through a 350 mm dry-zone atmosphere at a temperature of 30° C. anda relative humidity of 70% RH and then through a coagulation bath of 20%by weight of DMAc and 80% by weight of water at a temperature of 40° C.The hollow fiber membrane was then subjected to a water washing processat 60° C. for 90 seconds, and a crimping process. The resulting hollowfiber membrane (5) was wound into a bundle. The hollow fiber membranehad an inner diameter of 200 μm and a thickness of 40 μm. The shape of acrimp was determined, and it was found that the crimp had a wave heightof 0.3 mm (amplitude: 0.15 mm) and a wave length (pitch) of 8.0 mm.

Example 1

Nine thousand and seven hundred hollow fiber membranes 1-1 were insertedinto a case having an inner diameter of 36 mm, and the edge face part ofthe case was blown to disperse the hollow fiber membranes therein. Bothends of the hollow fiber membranes were respectively fixed to the edgeparts of the case with a potting material, and a portion of the end ofthe potting material was cut to open the hollow fiber membranes at theboth ends. The effective length of each of the hollow fiber membraneswas 26.4 cm. A header part was attached to the resulting product,thereby producing a hollow fiber membrane module (a). The hollow fibermembrane filling rate in a zone lying between the outermost peripheryand a position located 1 mm apart from the outermost periphery towardthe inner periphery in the edge face part was 47%, the hollow fibermembrane filling rate in a center part was 62%, wherein the differencebetween the filling rates was 15%. The Ra of the edge face part was 0.2μm, and the Ra of the inner surface of the header was 0.5 μm.

As the hydrophilic copolymerization polymer, a vinylpyrrolidone-vinylacetate copolymerization polymer (70/30 (by weight)) was used. Therelaxation time of the polymer at −40° C. was 2.2×10⁻⁸ seconds. A mixedaqueous solution of 0.01% by weight of the polymer and 0.1% by weight ofn-propanol was prepared, and the mixed aqueous solution was allowed topass from the blood side inlet Bi (22) toward the blood side outlet Bo(24) of the hollow fiber membrane module at 500 mL/min for 1 minute.Subsequently, the mixed aqueous solution was allowed to pass from theblood side inlet Bi (22) toward the dialyzate side inlet Di (12) at 500mL/min for 1 minute. In the aqueous solution used, dissolved oxygen wasremoved therefrom. The filling solution was pushed out from thedialyzate side toward the blood side with 100 kPa of compressed air, sothat the mixed aqueous solution did not remain in the module casebesides the hollow fiber membranes being in a moistened state. The watercontent in the hollow fiber membranes was 2.8 times the dried weight ofthe hollow fiber membranes.

Thereafter, the module was blown with nitrogen at a flow rate of 10mL/min at each of the dialyzate side and the blood side for 1 minute topurge the inside of the module with nitrogen, the module was thenplugged, and the module was irradiated with 25 kGy of γ-ray within 1week. The oxygen concentration in the module was 1%. The module wassubjected to various tests. In ESCA, since a vinylpyrrolidone-vinylacetate copolymerization polymer was used as the hydrophiliccopolymerization polymer, the amount of carbon derived from an estergroup can be observed. The ester (COO) carbon peak was observed at anenergy +4.0 to +4.2 eV higher than the main C1s peak derived from CH orC—C (at about 285 eV). Therefore, after peak deconvolution wasperformed, the ratio of the corresponding peak area to the peak area ofall elements (all elements except for the hydrogen atom, which was notdetectable) was calculated so that the ester carbon content (atm %) wasdetermined. Thus, there are two types of nitrogen atoms, i.e., anitrogen atom derived from PVP and a nitrogen atom derived from thevinylpyrrolidone-vinyl acetate copolymerization polymer, and the ratioof these two types of nitrogen atoms can be calculated on the basis ofthe amount of carbon derived from an ester group. Further, all of sulfuratoms are derived from polysulfone. From these results, the amount ofthe vinylpyrrolidone-vinyl acetate copolymerization polymer on thesurface can be calculated. In the case of avinylpyrrolidone-vinylcaprolactam copolymerization polymer or anethylene glycol-propylene glycol copolymerization polymer, the amountcan also be calculated from the amounts of carbon atoms, oxygen atoms,nitrogen atoms and sulfur atoms.

Example 2

A hollow fiber membrane module (a) that was produced in the same manneras in Example 1 was used, and a vinylpyrrolidone-vinyl acetatecopolymerization polymer (60/40 (by weight)) was used as the hydrophiliccopolymerization polymer. The relaxation time of the polymer was1.6×10⁻⁸ seconds at −40° C. An aqueous solution containing 0.01% byweight of the polymer was prepared, and the hollow fiber membranes weremoistened in the same manner as in Example 1, were then purged withnitrogen, and were then irradiated with 25 kGy of γ-ray within 1 week.The water content in the hollow fiber membranes was 2.7 times the driedweight of the hollow fiber membranes. The module was subjected tovarious tests.

Example 3

The hollow fiber membrane module (a) was used, and avinylpyrrolidone-vinyl acetate copolymerization polymer (50/50 (byweight)) was used as the hydrophilic copolymerization polymer. Therelaxation time of the polymer was 1.4×10⁻⁸ seconds at −40° C. A mixedaqueous solution containing 0.01% by weight of the polymer and 0.1% byweight of ethanol was prepared, and the hollow fiber membranes weremoistened in the same manner as in Example 1, were then purged withnitrogen, and were then irradiated with 25 kGy of γ-ray within 1 week.The water content in the hollow fiber membranes was 2.8 times the driedweight of the hollow fiber membranes. The module was subjected tovarious tests.

Example 4

Ten thousand hollow fiber membranes 1-2 were inserted into a case havingan inner diameter of 36 mm, and the edge face part of the case was blownto disperse the hollow fiber membranes therein. Both ends of the hollowfiber membranes were respectively fixed to the edge parts of the casewith a potting material, and a portion of the end of the pottingmaterial was cut to open the hollow fiber membranes at the both ends.The effective length of each of the hollow fiber membranes was 26.8 cm.A header part was attached to the resulting product, thereby producing ahollow fiber membrane module (b). The hollow fiber membrane filling ratein a zone lying between the outermost periphery and a position located 1mm apart from the outermost periphery toward the inner periphery in theedge face part was 30%, the hollow fiber membrane filling rate in acenter part was 58%, wherein the difference between the filling rateswas 28%. The overall filling rate was 53%. The Ra of the edge face partwas 0.2 μm, and the Ra of the inner surface of the header was 0.5 μm.

Subsequently, the inside of the module was purged with nitrogen in thesame manner as in Example 1 without moistening the hollow fibermembranes, and the module was irradiated with 25 kGy of electron beamwithin 1 week. The oxygen concentration in the module was 1%. The modulewas subjected to various tests.

Example 5

Nine thousand and six hundred hollow fiber membranes 3 were insertedinto a case having an inner diameter of 36 mm, and the edge face part ofthe case was blown to disperse the hollow fiber membranes therein. Bothends of the hollow fiber membranes were respectively fixed to the edgeparts of the case with a potting material, and a portion of the end ofthe potting material was cut to open the hollow fiber membranes at theboth ends. The effective length of each of the hollow fiber membraneswas 26.3 cm. A header part was attached to the resulting product,thereby producing a hollow fiber membrane module (c). The hollow fibermembrane filling rate in a zone lying between the outermost peripheryand a position located 1 mm apart from the outermost periphery towardthe inner periphery in the edge face part was 48%, the hollow fibermembrane filling rate in a center part was 63%, wherein the differencebetween the filling rates was 15%. The overall filling rate was 58%. TheRa of the edge face part was 0.2 μm, and the Ra of the inner surface ofthe header was 0.5 μm.

Subsequently, the inside of the module was purged with nitrogen in thesame manner as in Example 1 without moistening the hollow fibermembranes, and the module was irradiated with 25 kGy of γ-ray within 1week. The oxygen concentration in the module was 1%. The module wassubjected to various tests.

Example 6

The hollow fiber membranes 2-2 were used, and about 9600 the hollowfiber membranes were bound up to produce a hollow fiber membrane bundle40. The hollow fiber membrane bundle was inserted into a polypropylenecase (a main body case 10) having a full length of 282 mm, a body innerdiameter D1 of 35.1 mm, an edge part inner diameter of 39.3 mm and abody length of 237 mm in such a manner that both ends of the bundleprotruded outside of the main body case 10. The hollow fiber membranefilling rate in the body part of the main body case was 61.1%.Subsequently, parts around the outer peripheries of the both ends of thehollow fiber membrane bundle 40 protruded from the main body case 10were air-blown at a flow rate of 1.5 L/min using a Taslan nozzle todiffuse the hollow fiber membrane bundle. Each of the both ends of thehollow fiber membrane bundle was bundled together using a cover platethat was formed by bonding two plates each having a semicircular cutoutsection together and had a diameter of 38 mm, a carbon dioxide laserhaving an output level of 80 W was defocused to an edge face toirradiate the edge face with the laser at a predetermined pattern,thereby sealing the hollow part of the hollow fiber membrane 41.Subsequently, a cap having a length that was enough to get stuck in thecenter part of the edge face of the hollow fiber membrane bundle and didnot reach each of subsequently-formed partitioning walls 31 and 33 ofthe edge faces and equipped with a tip-sharp protrusion was attached toeach of both ends of the main body case 10, a urethane resin wasinjected through a dialyzate inlet port 12 and a dialyzate outlet port13 and then cured under centrifugation to thereby form the partitioningwalls 30 and 32, thereby fixing the hollow fiber membrane bundle 40 tothe inner walls of both edge parts of the main body case 10. Each of thepartitioning walls 30 and 32 thus formed was cut with a sharp cutter ata position 1.5 mm apart from each of the ends of the main body case 10,thereby forming an edge face of each of the partitioning walls 31 and 33and opening the hollow fiber membrane 41. Images of the edge faces ofthe partitioning walls 31 and 33 were taken using a camera, and thehollow fiber membrane filling rate in each of the zones A to H wascalculated. Subsequently, headers 21 and 23 each having an edge innerdiameter D0 of 37.3 mm were welded to the main body case 10 by applyingultrasonic wave, plugs were attached thereto, and the resulting productwas packaged and then sterilized by the irradiated with 25 kGy of γ-ray,thereby completing a hollow fiber membrane module (d-1). The hollowfiber membrane module was used to carry out various tests.

Example 7

The same procedure as in Example 6 was carried out, except using hollowfiber membranes 2-3, thereby producing a hollow fiber membrane module(d-2). The hollow fiber membrane module was used to carry out varioustests.

Example 8

The same procedure as in Example 6 was carried out, except that a coverplate produced using two plates each having a semicircular cutoff partand having a diameter of 33.8 mm for the sealing of the hollow part wasused and headers 21 and 23 each having a header inner diameter D0 of35.1 mm was used, thereby producing a hollow fiber membrane module (e).The hollow fiber membrane module was used to carry out various tests.

Example 9

The same procedure as in Example 6 was carried out, except using hollowfiber membranes 1-2, thereby producing a hollow fiber membrane module(d-3). However, in this example, prior to the irradiation with γ-ray, avinylpyrrolidone-vinylcaprolactam copolymerization polymer (50/50 (byweight)) was used as the hydrophilic copolymerization polymer, a mixedaqueous solution of 0.01% by weight of the polymer and 0.1% by weight ofethanol was prepared, and the mixed aqueous solution was allowed to passfrom the blood side inlet Bi (22) toward the blood side outlet Bo (24)of the hollow fiber membrane module at 500 mL/min for 1 minute.Subsequently, the mixed aqueous solution was allowed to pass from theblood side inlet Bi (22) toward the dialyzate side inlet Di (12) at 500mL/min for 1 minute. In the aqueous solution used, dissolved oxygen wasremoved therefrom. The filling solution was pushed out from thedialyzate side toward the blood side with 100-kPa compressed air andthen the solution located on the blood side was blown while keeping thedialyzate side in a pressurized state, so that the mixed aqueoussolution did not remain in the module case besides the hollow fibermembranes being in a moistened state. The water content in the hollowfiber membranes was 2.8 times the dried weight of the hollow fibermembranes.

Thereafter, the module was blown with nitrogen at a flow rate of 10mL/min at each of the dialyzate side and the blood side for 1 minute topurge the inside of the module with nitrogen, the module was thenplugged, and the module was irradiated with 25 kGy of γ-ray within 1week. The oxygen concentration in the module was 1%. The module wassubjected to various tests.

Example 10

A γ-ray-irradiated hollow fiber membrane module was produced in the samemanner as in Example 9, except that hollow fiber membranes 1-2 were usedand an ethylene glycol-propylene glycol copolymerization polymer (20/80(by weight)) was used as the hydrophilic copolymerization polymer. Therelaxation time of the polymer was 1.5×10⁻⁸ seconds at −40° C. A mixedaqueous solution containing 0.01% by weight of the polymer and 0.1% byweight of ethanol was prepared, and the hollow fiber membranes weremoistened in the same manner as in Example 1, were then purged withnitrogen, and were then irradiated with 25 kGy of γ-ray within 1 week.The water content in the hollow fiber membranes was 2.8 times the driedweight of the hollow fiber membranes. The module was subjected tovarious tests.

Example 11

A hollow fiber membrane module was produced in the same manner as inExample 1, except that a vinylpyrrolidone-vinylcaprolactamcopolymerization polymer (50/50 (by weight)) was used as the hydrophiliccopolymerization polymer and a mixed aqueous solution containing 1% byweight of the polymer and 0.1% by weight of n-propanol was prepared andthe same procedures were carried out. However, in this example, thefilling solution was pushed out from the dialyzate side toward the bloodside with 0.2 MPa of compressed air and then the solution located on theblood side was blown at a maximum pressure of 0.2 MPa, a minimumpressure of 0.1 MPa, a flow rate of 20 L (Normal)/min and an airapplication frequency of 1 time/sec (blowing air five times at themaximum pressure/minimum pressure for 5 seconds; i.e., blowing air atthe maximum pressure for 0.5 seconds and blowing air at the minimumpressure for 0.5 seconds), while keeping the pressure in the dialyzateside at 0.2 MPa, thereby removing an excess portion of thecopolymerization polymer and rendering only the hollow fiber membranesin a moistened state. The water content in the hollow fiber membraneswas 2.8 times the dried weight of the hollow fiber membranes.

Thereafter, the module was blown with nitrogen at a flow rate of 10mL/min at each of the dialyzate side and the blood side for 1 minute topurge the inside of the module with nitrogen, the module was thenplugged, and the module was irradiated with 25 kGy of γ-ray within 1week. The oxygen concentration in the module was 1%. The module wassubjected to various tests.

Comparative Example 1

A hollow fiber membrane module (a) produced in the same manner as inExample 1 was used, but only a matter that PVP (ISP) K90 was used inplace of the hydrophilic copolymerization polymer was different. Therelaxation time of the PVP was 2.6×10⁻⁸ seconds at −40° C. An aqueoussolution containing 0.01% by weight of the PVP was prepared, and thehollow fiber membranes were moistened in the same manner as in Example1, were then purged with nitrogen, and were then irradiated with 25 kGyof electron beam within 1 week. The water content in the hollow fibermembranes was 2.7 times the dried weight of the hollow fiber membranes.The module was subjected to various tests.

Comparative Example 2

Ten thousand hollow fiber membranes 4 were inserted into a case havingan inner diameter of 40 mm, and the edge face part of the case was blownto disperse the hollow fiber membranes therein. Both ends of the hollowfiber membranes were respectively fixed to the edge parts of the casewith a potting material, and a portion of the edge part of the pottingmaterial was cut to open the hollow fiber membranes at the both ends.The effective length of each of the hollow fiber membranes was 26.4 cm.A header part was attached to the resulting product, thereby producing ahollow fiber membrane module (g). The hollow fiber membrane filling ratein a position located 1 mm apart from the outermost periphery toward theinner periphery in the edge face was 22%, the hollow fiber membranefilling rate in a center part was 52%, wherein the difference betweenthe filling rates was 30%. The overall filling rate was 49%. The Ra ofthe edge face part was 0.9 μm, and the Ra of the inner surface of theheader was 0.5 μm.

As the hydrophilic copolymerization polymer, a vinylpyrrolidone-vinylacetate copolymerization polymer (70/30 (by weight)) was used. Anaqueous solution containing 0.01% by weight of the polymer was prepared,and the hollow fiber membranes were moistened in the same manner as inExample 1, were then purged with nitrogen, and were then irradiated with25 kGy of γ-ray within 1 week. The water content in the hollow fibermembranes was 2.7 times the dried weight of the hollow fiber membranes.The module was subjected to various tests.

Comparative Example 3

The same procedure as in Example 6 was carried out, except that a coverplate produced using two plates each having a semicircular cutoff partand having a diameter of 36 mm for the sealing of the hollow part wasused, thereby producing a hollow fiber membrane module (d-4). The hollowfiber membrane module was used to carry out various tests.

Comparative Example 4

The same procedure as in Example 6 was carried out, except that airblowing was not carried out, thereby producing a hollow fiber membranemodule (d-5). The hollow fiber membrane module was used to carry outvarious tests.

Comparative Example 5

The same procedure as in Example 6 was carried out, except that a coverplate produced using two plates each having a semicircular cutoff partand having a diameter of 45 mm for the sealing of the hollow part wasused, headers 21 and 23 each having a header inner diameter DO of 44.3mm were used, and a main body case 10 having an edge part inner diameterof 46.3 mm was used, thereby producing a hollow fiber membrane module(h). The hollow fiber membrane module was used to carry out varioustests.

Comparative Example 6

A γ-ray-irradiated hollow fiber membrane module was produced in the samemanner as in Example 9, except that hollow fiber membranes 1-2 were usedand PVP (ISP) K90 was used in place of the hydrophilic copolymerizationpolymer. The hollow fiber membranes were moistened in the same manner asin Example 1, were then purged with nitrogen, and were then irradiatedwith 25 kGy of γ-ray within 1 week. The water content in the hollowfiber membranes was 2.8 times the dried weight of the hollow fibermembranes. The module was subjected to various tests.

Comparative Example 7

The same procedure as in Example 1 was carried out, except that avinylpyrrolidone-vinylcaprolactam copolymerization polymer (50/50 (byweight)) was used as the hydrophilic copolymerization polymer and theconcentration of the polymer employed was 1% by weight. Since thedischarge of the aqueous solution was also carried out in the samemanner as in Example 1, the conditions employed in this comparativeexample were those which could cause unevenness readily. Within 1 weekafter the purging with nitrogen, the module was irradiated with 25 kGyof γ-ray. The water content in the hollow fiber membranes was 2.8 timesthe dried weight of the hollow fiber membranes. The module was subjectedto various tests.

TABLE 1 Amount of copolymerization Inner Number of Polymer Compositionof inner Introduction of Relaxation polymer surface Particulateplatelets Residual composition of injection diameter/ wave height/hydrophilic time of [wt %] flexible protuberances adhered blood testHF¹⁾ stock solution²⁾ solution thickness wavelength MD³⁾copolymerization adsorbed Inner Outer layer [particles/ [particles/[fiber No [wt %] [wt %] [μm] [mm] No polymer⁴⁾ water [sec] surfacesurface [nm] μm²] (4.3 × 10³ μm²)] membranes] Example 1 1-1PSf/PVP(K30)/ DMAc/water 195/40 0.3/8.0 a Membranes were 2.2 × 10⁻⁸ 13N.D. 10 0.3 18 6 PVP(K90) 65/35 irradiated with γ-ray in 16/4/2 mixedaqueous VP/VAc(70/30) + Pro solution Example 2 1-1 PSf/PVP(E30)/DMAc/water 195/40 0.3/8.0 a Membranes were 1.6 × 10⁻⁸ 18 N.D. 15 0.3 0.20 PVP(K90) 65/35 irradiated with γ-ray in 16/4/2 aqueous VP/VAc(60/40)solution Example 3 1-1 PSf/PVP(K30)/ DMAc/water 195/40 0.3/8.0 aMembranes were 1.4 × 10⁻⁸ 33 N.D. 16 0.3 0.2 0 PVP(K90) 65/35 irradiatedwith γ-ray in 16/4/2 mixed aqueous VP/VAc(50/50) + Et solution Example 42-1 PSf/PVP(K30)/ DMAc/water/ 185/38 0.4/8.0 b VP/VAc(60/40) was added1.6 × 10⁻⁸ 15 N.D. 14 0.2 0.5 1 PVP(K90) VA64 to injection solution16/4/2 63/37/10 Example 5 3 PSf/VA64 DMAc/water 200/40 0.3/7.0 cVP/VAc(60/40) was added 1.6 × 10⁻⁸ 19 9 15 0.1 1 0 18/9 60/40 tospinning solution Example 6 2-2 PSf/PVP(K30)/ DMAc/water/ 200/40 0.2/8.0d-1 VP/VAc(60/40) was added 1.6 × 10⁻⁸ 15 N.D. 14 0.2 0.5 0 PVP(K90)VA64 to injection solution 16/4/2 63/37/10 Example 7 2-3 PSf/PVP(K30)/DMAc/water/ 200/40 1.7/17 d-2 VP/VAc(60/40) was added 1.6 × 10⁻⁸ 15 N.D.14 0.2 0.5 1 PVP(K90) VA64 to injection solution 16/4/2 63/37/10 Example8 2-2 PSf/PVP(K30)/ DMAc/water/ 200/40 0.2/8.0 e VP/VAc(60/40) was added1.6 × 10⁻⁸ 15 N.D. 14 0.2 0.5 1 PVP(K90) VA64 to injection solution16/4/2 63/37/10 Example 9 1-2 PSf/PVP(K30)/ DMAc/water 200/40 0.2/8.0d-3 Membranes were 1.0 × 10⁻⁸ 22 N.D. 15 0.3 1 1 PVP(K90) 65/35irradiated with γ-ray in 16/4/2 mixed aqueous VP/VC(50/50) + Et solutionExample 10 1-2 PSf/PVP(K30)/ DMAc/water 200/40 0.2/8.0 d-3 Membraneswere 1.5 × 10⁻⁸ 18 N.D. 15 0.3 0.3 1 PVP(K90) 65/35 irradiated with γ-16/4/2 ray in mixed aqueous EG/PG(20/80) + Et solution Example 11 1-1PSf/PVP(K30)/ DMAc/water 195/40 0.3/8.0 a Membranes were 1.0 × 10⁻⁸ 28N.D. 16 0.4 0.4 1 PVP(K90) 65/35 irradiated with γ- 16/4/2 ray in mixedaqueous VP/VC(50/50) + Pro solution Comparative 1-1 PSf/PVP(K30)/DMAc/water 195/40 0.4/8.0 a None (Membranes were 2.6 × 10⁻⁸ — — 5 0.3 7025 Example 1 PVP(K90) 65/35 irradiated with γ- 16/4/2 ray in mixedaqueous PVP + Et solution) Comparative 4 PSf/K90 DMAc/water 190/450.4/8.0 g Membranes were 2.2 × 10⁻⁸ 13 N.D. 10 4.1 40 20 Example 2 17/557/43 irradiated with γ- ray in aqueous VP/VAc(70/30) solutionComparative 2-2 PSf/PVP(K30)/ DMAc/water/ 200/40 0.2/8.0 d-4VP/VAc(60/40) was 1.6 × 10⁻⁸ 15 N.D. 14 0.2 0.5 more than Example 3PVP(K90) VA64 added to injection 50 16/4/2 63/37/10 solution Comparative2-2 PSf/PVP(K30)/ DMAc/water/ 200/40 0.2/8.0 d-5 VP/VAc(60/40) was 1.6 ×10⁻⁸ 15 N.D. 14 0.2 0.5 12 Example 4 PVP(K90) VA64 added to injection16/4/2 63/37/10 solution Comparative 2-2 PSf/PVP(K30)/ DMAc/water/200/40 0.2/8.0 h VP/VAc(60/40) was 1.6 × 10⁻⁸ 15 N.D. 14 0.2 0.5 morethan Example 5 PVP(K90) VA64 added to injection 50 16/4/2 63/37/10solution Comparative 1-2 PSf/PVP(K30)/ DMAc/water 200/40 0.2/8.0 d-3None (Membranes were 2.6 × 10⁻⁸ — — 5 0.3 67 20 Example 6 PVP(K90) 65/35irradiated with γ- 16/4/2 ray in mixed aqueous PVP + Et solution)Comparative 1-1 PSf/PVP(K30)/ DMAc/water 195/40 0.3/8.0 a Membranes were1.0 × 10⁻⁸ 33 N.D. 17 3.3 30 15 Example 7 PVP(K90) 65/35 irradiated withγ- 16/4/2 ray in mixed aqueous VP/VC(50/50) + Pro solution ¹⁾HF:abbreviation for hollow fiber membrane, ²⁾PSf: abbreviation forpolysulfone, PVP: abbreviation for polyvinylpyrrolidone, ³⁾MD:abbreviation for hollow fiber membrane module, ⁴⁾VP: abbreviation forvinylpyrrolidone, VAc: abbreviation for vinyl acetate, VC: abbreviationfor vinylcaprolactam, Pro: abbreviation for n-propanol, Et: abbreviationfor ethanol, EG: abbreviation for ethylele glycol, PG: abbreviation forpropylene glycol

TABLE 2 Difference in filling Filling rate between Ra of rate in Fillingoutermost edge Ra of Sc- outermost rate in periphery face header Sc- Sc-Alb(20)/ periphery center and center part part Alb(5) Alb(20) Sc- [%]part [%] part [%] [μm] [μm] [%] [%] Alb(5) Example 1 47 62 15 0.2 0.51.01 0.77 0.76 Example 2 47 62 15 0.2 0.5 0.88 0.73 0.83 Example 3 47 6215 0.2 0.5 0.75 0.66 0.88 Example 4 30 58 28 0.2 0.5 0.98 0.77 0.79Example 5 48 63 15 0.2 0.5 1.65 1.22 0.74 Comparative 47 62 15 0.2 0.51.5 0.83 0.55 Example 1 Comparative 22 52 30 0.9 0.5 4.24 2.04 0.48Example 2 Sc-β₂MG Sc-β₂MG Sc-β₂MG(20)/ Ko(W) Ko(B) Ko(B)/ (5) [%] (20)[%] Sc-β₂MG(5) [cm/min] [cm/min] Ko(W) Example 1 72.7 84.1 1.16 0.07110.0569 0.80 Example 2 74.7 83.4 1.12 0.0666 0.0618 0.93 Example 3 75.582.7 1.10 0.0612 0.0570 0.93 Example 4 76.6 85.2 1.11 0.0666 0.0597 0.90Example 5 78.8 89.2 1.13 0.0687 0.0612 0.89 Comparative 68.9 83.2 1.210.0711 0.0505 0.71 Example 1 Comparative 78.8 91.7 1.16 0.0711 0.05570.78 Example 2

TABLE 3 Case body Fiber Header part bundle Filling Filling inner innerouter rate in rate in diameter diameter diameter Crimp edge body D0 D1D2 amplitude W pitch P face part [mm] [mm] [mm] D0/D1 [mm] [mm] [%] [%]Example 6 37.3 35.1 36.7 1.063 0.1 8 54.1 61.1 Example 7 37.3 35.1 36.31.063 0.85 17 54.1 61.1 Example 8 35.1 35.1 34.3 1.000 0.1 8 61.1 61.1Example 9 37.3 35.1 36.7 1.063 0.1 8 54.1 61.1 Example 10 37.3 35.1 36.71.063 0.1 8 54.1 61.1 Comparative 37.3 35.1 35.4 1.063 0.1 8 54.1 61.1Example 3 Comparative 37.3 35.1 36.7 1.063 0.1 8 54.1 61.1 Example 4Comparative 44.3 35.1 41.2 1.262 0.1 8 38.4 61.1 Example 5 Comparative37.3 35.1 36.7 1.063 0.1 8 54.1 61.1 Example 6 Residual Filling rate ineach zone¹⁾ [%] blood aver- test Urea CL A B C D E F G H age [tube][mL/min] Example 6 28.6 29.5 33.9 22.4 24.7 27.7 30.4 30.4 28.5 0 19834.3 30.8 19.4 33.5 30.8 21.6 24.2 34.3 28.6 Example 7 15.8 17.6 20.120.4 15.6 14.7 18.3 15.0 17.2 1 196 25.1 15.9 13.7 15.0 18.9 15.4 18.422.5 18.1 Example 8 15.6 15.0 17.6 15.4 15.9 18.1 20.3 15.3 16.7 1 19217.2 16.7 22.5 22.9 24.7 18.9 19.4 21.5 20.5 Example 9 25.0 33.2 31.527.7 25.5 26.2 25.7 32.2 28.4 1 197 35.3 31.2 30.3 25.5 27.8 28.8 25.326.8 28.9 Example 10 19.0 30.5 31.1 23.3 24.3 33.5 32.2 31.2 28.1 1 19733.4 29.0 24.3 20.4 30.6 27.5 22.2 30.9 27.3 Comparative 2.2 0.0 0.910.6 5.7 0.0 0.0 4.8 3.0 more 195 Example 3 1.3 0.4 0.0 7.9 13.2 0.4 0.40.0 3.0 than 50 Comparative 29.0 9.9 4.2 18.6 31.8 19.2 17.7 17.8 18.512  197 Example 4 15.0 18.1 15.4 16.3 6.6 8.4 12.3 7.9 12.5 Comparative4.2 0.0 0.0 3.5 6.7 0.0 0.0 2.6 2.1 more 197 Example 5 16.3 5.7 0.4 2.61.8 0 2.2 7.1 4.5 than 50 Comparative 33.3 29.3 23.3 32.4 27.0 25.3 30.129.9 28.8 20  196 Example 6 26.6 28.7 20.8 30.5 29.9 34.9 22.1 34.1 28.5¹⁾Uppper column: dividing wall edge face on blood inlet side (FIG.1-31), lower column: dividing wall edge face on blood outlet side (FIG.1-33)

DESCRIPTION OF REFERENCE SIGNS

-   -   1: Blood treatment apparatus    -   2: Case    -   3: Potting agent    -   4: Blood side inlet (Bi)    -   5: Blood side outlet (Do)    -   6: Dialyzate side inlet (Di)    -   7: Dialyzate side outlet (Do)    -   8: Hollow fiber membrane    -   10: Main body case    -   11: Baffle    -   12: Dialyzate inlet port    -   13: Dialyzate outlet port    -   21: Blood inlet header    -   22: Blood inlet port    -   23: Blood outlet header    -   24: Blood outlet port    -   25: Contact surface of header with partitioning wall    -   27, 28: Header internal space    -   30, 32: Partitioning wall    -   31, 33: Edge surface of partitioning wall    -   40: Hollow fiber membrane bundle    -   41: Hollow fiber membrane    -   58: Base line    -   59: Dialyzer    -   61: Bi pump    -   62: F pump    -   63: Waste container    -   64: Blood for circulation    -   65: Blood for clearance measurement    -   66: Bi circuit    -   67: Bo circuit    -   68: Di circuit    -   69: Do circuit    -   70: Warm water tank

1. A medical material having a hydrophilic copolymerization polymerpresent on a surface thereof which is to be in contact with blood,wherein particulate protuberances each having a particle diameter of 50nm or more are present on the surface which is to be in contact withblood at a density of 3 particles/μm² or less and the relaxation time ofadsorbed water in the hydrophilic copolymerization polymer is 2.5×10⁻⁸seconds or shorter and 5.0×10⁻¹⁰ seconds or longer at −40° C.
 2. Themedical material according to claim 1, wherein a flexible layer ispresent on the surface which is to be in contact with blood when thematerial is in a moistened state and the flexible layer has a thicknessof 7 nm or more.
 3. The medical material according to claim 1, whereinthe amount of the hydrophilic copolymerization polymer on the surfacewhich is to be in contact with blood is 5 to 30% by weight inclusive. 4.The medical material according to claim 1, wherein the medical materialhas a form of a hollow fiber membrane.
 5. The medical material accordingto claim 1, wherein a polysulfone-type polymer is used.
 6. A hollowfiber membrane module having a medical material as recited in claim 4incorporated therein.
 7. The hollow fiber membrane module according toclaim 6, wherein the hollow fiber membrane filling rate in a zone lyingbetween an outermost periphery and a position located 1 mm apart fromthe outermost periphery toward an inner periphery in an edge face partis 15% or more and the difference between the hollow fiber membranefilling rate in the zone and that in a center part is 40% or less.
 8. Ahollow fiber membrane module comprising: a hollow fiber membrane bundlewhich is composed of hollow fiber membranes each having, on a surfacethereof which is to be in contact with blood, a hydrophiliccopolymerization polymer having a relaxation time of adsorbed water of2.5×10⁻⁸ seconds or shorter and 5.0×10⁻¹⁰ or longer at −40° C.; a mainbody case in which the hollow fiber membrane bundle is stored;partitioning walls which enable the hollow fiber membrane bundle to beheld in a liquid-tight state at both ends of the main body case whilekeeping the hollow part edge faces in an opened state; and headers whichare respectively attached to both ends of the main body case and throughwhich blood can be introduced and led out; wherein the hollow fibermembrane filling rate in each of zones A to H, which are zones producedby dividing a zone lying between a position corresponding to the innerdiameter D0 of each of the headers and a position 1 mm apart from theaforementioned position toward the inner periphery into equal 8 partsequiangular with the center of axis of the main body case as its centerin an edge face of each of the partitioning walls on a side facing eachof the headers, falls within the range from 13 to 40%.
 9. The hollowfiber membrane module according to claim 8, wherein particulateprotuberances each having a particle diameter of 50 nm or more arepresent on the surface which is to be in contact with blood in each ofthe hollow fiber membranes at a density of 3 particles/μm² or less. 10.The hollow fiber membrane module according to claim 8, wherein aflexible layer is present on the surface which is to be in contact withblood in each of the hollow fiber membranes when the material is in amoistened state and the flexible layer has a thickness of 7 nm or more.11. The hollow fiber membrane module according to claim 8, wherein theamount of the hydrophilic copolymerization polymer on the surface whichis to be in contact with blood in each of the hollow fiber membranes is5 to 30% by weight inclusive.